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Stem Cell Extension Study Reinforces Signal of Benefit for Progressive MS
WEST PALM BEACH, FLORIDA — , according to data presented as a late-breaker at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
After at least 1 year of follow-up in 23 patients participating in the extension analysis, “there has been favorable effects on cognitive function, neurological functional tests, quality of life, and both of two major biomarkers linked to neurodegeneration,” reported Dimitrios Karussis, MD, PhD, Chairman of the Multiple Sclerosis Center, Hadassah Hospital, Jerusalem.
Based on promising preclinical studies, the initial clinical study with MSCs was published in Brain in 2020. In that study, 48 participants were randomized to receive an intrathecal injection of MSCs, an intravenous injection of MSCs, or a sham injection. The MSCs were collected from the bone marrow of each participant and cultured.
A second injection in the active treatment groups was administered at 6 months. At this time, those initially randomized to a sham injection received either an intrathecal or an IV injection of MSCs harvested from their bone marrow.
No Disease Activity Seen in 60% at 1 Year
When evaluated at the end of 1 year, there was no evidence of disease activity in 58.6% of those receiving the two intrathecal injections of MSCs, 40.6% of those receiving two IV injections of MSCs, and 9.7% of those initially randomized to the sham group. The intrathecal injection of MSCs, which was well tolerated, appeared to offer greater efficacy and was associated with relative benefits on multiple additional measures, including reduced T2 lesion load, lower relapse rates, and sustained cognitive function.
Forty of the patients in the initial study were enrolled in the extension. In the late-breaker presentation, Dr. Karussis provided interim results on 23, of which all had been followed for at least another additional year. These patients had been treated with one to three intrathecal injects of MSCs at intervals of 3 to 6 months.
Of further gains during the extension, Dr. Karussis described gains in cognitive function, represented by a 3-degree improvement in the Symbol Digit Modalities Test (SDMT), a median 17% improvement in the 25-foot walk test, and an improvement in quality of life, captured in domains of both physical and mental function. All of these gains were statistically significant.
The clinical responses were supported by reductions in both serum neurofilament light chain (sNfL) levels and in the glial fibrillary acid protein (GFAP), which Dr. Karussis described as important biomarkers of disease progression. For sNfL, the reduction was 33.2% (P = .001), and there was further decline observed after repeated MSC injections.
The 22% (P < .0004) reduction in GFAP, which Dr. Karussis said has not been shown before, was observed in all 23 patients. Again, there was an additional reduction with repeated MSC treatments.
The safety and tolerability remained encouraging with longer follow-up. As in the original series, there were no serious adverse events. Headache and backache, which were more common among those receiving intrathecal injections of MSC in the original study, continued to be reported in the extension, but these were time-limited.
Although Dr. Karussis emphasized that these interim results await confirmation with longer follow-up and larger studies, he suggested that the consistency of benefit with early report provides “an additional hint of possible neuroprotective and neurotrophic effects.”
Mechanism of MSC Benefit Incompletely Documented
In patients with progressive MS, there is an urgent need for more and better therapies. MSCs, which reside primarily in bone marrow but can be found in other tissues, have been associated with immunomodulatory as well as neuroprotective effects in experimental studies, but whether one or the other or both of these activities are responsible for the clinical benefits observed so far is unresolved.
Others evaluating MSCs in the experimental setting have shown that these “produce a variety of soluble factors with immunomodulatory, neuroprotective, and repair-promoting properties,” said Jeffrey A. Cohen, MD, who was asked to comment on the findings. Dr. Cohen is director of the experimental therapeutics program at the Mellen Center for Multiple Sclerosis, Cleveland Clinic. He said that previous experimental work has encouraged clinical studies, including the work presented by Dr. Karussis.
While the late-breaker presentation provided data suggesting “persistent potent efficacy with good safety and tolerability,” Dr. Cohen pointed out that “the results from this group are substantially better than those reported by several other groups.” He called the difference in results “uncertain,” suggesting that more work is needed to prove that clinical benefit is reliably achieved.
“I think it is too early to tell if MSC transplantation is going to be useful. Other than [the data] reported by the Karussis group, the results have been rather disappointing,” Dr. Cohen said.
Dr. Karussis reports no potential conflicts of interest.
WEST PALM BEACH, FLORIDA — , according to data presented as a late-breaker at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
After at least 1 year of follow-up in 23 patients participating in the extension analysis, “there has been favorable effects on cognitive function, neurological functional tests, quality of life, and both of two major biomarkers linked to neurodegeneration,” reported Dimitrios Karussis, MD, PhD, Chairman of the Multiple Sclerosis Center, Hadassah Hospital, Jerusalem.
Based on promising preclinical studies, the initial clinical study with MSCs was published in Brain in 2020. In that study, 48 participants were randomized to receive an intrathecal injection of MSCs, an intravenous injection of MSCs, or a sham injection. The MSCs were collected from the bone marrow of each participant and cultured.
A second injection in the active treatment groups was administered at 6 months. At this time, those initially randomized to a sham injection received either an intrathecal or an IV injection of MSCs harvested from their bone marrow.
No Disease Activity Seen in 60% at 1 Year
When evaluated at the end of 1 year, there was no evidence of disease activity in 58.6% of those receiving the two intrathecal injections of MSCs, 40.6% of those receiving two IV injections of MSCs, and 9.7% of those initially randomized to the sham group. The intrathecal injection of MSCs, which was well tolerated, appeared to offer greater efficacy and was associated with relative benefits on multiple additional measures, including reduced T2 lesion load, lower relapse rates, and sustained cognitive function.
Forty of the patients in the initial study were enrolled in the extension. In the late-breaker presentation, Dr. Karussis provided interim results on 23, of which all had been followed for at least another additional year. These patients had been treated with one to three intrathecal injects of MSCs at intervals of 3 to 6 months.
Of further gains during the extension, Dr. Karussis described gains in cognitive function, represented by a 3-degree improvement in the Symbol Digit Modalities Test (SDMT), a median 17% improvement in the 25-foot walk test, and an improvement in quality of life, captured in domains of both physical and mental function. All of these gains were statistically significant.
The clinical responses were supported by reductions in both serum neurofilament light chain (sNfL) levels and in the glial fibrillary acid protein (GFAP), which Dr. Karussis described as important biomarkers of disease progression. For sNfL, the reduction was 33.2% (P = .001), and there was further decline observed after repeated MSC injections.
The 22% (P < .0004) reduction in GFAP, which Dr. Karussis said has not been shown before, was observed in all 23 patients. Again, there was an additional reduction with repeated MSC treatments.
The safety and tolerability remained encouraging with longer follow-up. As in the original series, there were no serious adverse events. Headache and backache, which were more common among those receiving intrathecal injections of MSC in the original study, continued to be reported in the extension, but these were time-limited.
Although Dr. Karussis emphasized that these interim results await confirmation with longer follow-up and larger studies, he suggested that the consistency of benefit with early report provides “an additional hint of possible neuroprotective and neurotrophic effects.”
Mechanism of MSC Benefit Incompletely Documented
In patients with progressive MS, there is an urgent need for more and better therapies. MSCs, which reside primarily in bone marrow but can be found in other tissues, have been associated with immunomodulatory as well as neuroprotective effects in experimental studies, but whether one or the other or both of these activities are responsible for the clinical benefits observed so far is unresolved.
Others evaluating MSCs in the experimental setting have shown that these “produce a variety of soluble factors with immunomodulatory, neuroprotective, and repair-promoting properties,” said Jeffrey A. Cohen, MD, who was asked to comment on the findings. Dr. Cohen is director of the experimental therapeutics program at the Mellen Center for Multiple Sclerosis, Cleveland Clinic. He said that previous experimental work has encouraged clinical studies, including the work presented by Dr. Karussis.
While the late-breaker presentation provided data suggesting “persistent potent efficacy with good safety and tolerability,” Dr. Cohen pointed out that “the results from this group are substantially better than those reported by several other groups.” He called the difference in results “uncertain,” suggesting that more work is needed to prove that clinical benefit is reliably achieved.
“I think it is too early to tell if MSC transplantation is going to be useful. Other than [the data] reported by the Karussis group, the results have been rather disappointing,” Dr. Cohen said.
Dr. Karussis reports no potential conflicts of interest.
WEST PALM BEACH, FLORIDA — , according to data presented as a late-breaker at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
After at least 1 year of follow-up in 23 patients participating in the extension analysis, “there has been favorable effects on cognitive function, neurological functional tests, quality of life, and both of two major biomarkers linked to neurodegeneration,” reported Dimitrios Karussis, MD, PhD, Chairman of the Multiple Sclerosis Center, Hadassah Hospital, Jerusalem.
Based on promising preclinical studies, the initial clinical study with MSCs was published in Brain in 2020. In that study, 48 participants were randomized to receive an intrathecal injection of MSCs, an intravenous injection of MSCs, or a sham injection. The MSCs were collected from the bone marrow of each participant and cultured.
A second injection in the active treatment groups was administered at 6 months. At this time, those initially randomized to a sham injection received either an intrathecal or an IV injection of MSCs harvested from their bone marrow.
No Disease Activity Seen in 60% at 1 Year
When evaluated at the end of 1 year, there was no evidence of disease activity in 58.6% of those receiving the two intrathecal injections of MSCs, 40.6% of those receiving two IV injections of MSCs, and 9.7% of those initially randomized to the sham group. The intrathecal injection of MSCs, which was well tolerated, appeared to offer greater efficacy and was associated with relative benefits on multiple additional measures, including reduced T2 lesion load, lower relapse rates, and sustained cognitive function.
Forty of the patients in the initial study were enrolled in the extension. In the late-breaker presentation, Dr. Karussis provided interim results on 23, of which all had been followed for at least another additional year. These patients had been treated with one to three intrathecal injects of MSCs at intervals of 3 to 6 months.
Of further gains during the extension, Dr. Karussis described gains in cognitive function, represented by a 3-degree improvement in the Symbol Digit Modalities Test (SDMT), a median 17% improvement in the 25-foot walk test, and an improvement in quality of life, captured in domains of both physical and mental function. All of these gains were statistically significant.
The clinical responses were supported by reductions in both serum neurofilament light chain (sNfL) levels and in the glial fibrillary acid protein (GFAP), which Dr. Karussis described as important biomarkers of disease progression. For sNfL, the reduction was 33.2% (P = .001), and there was further decline observed after repeated MSC injections.
The 22% (P < .0004) reduction in GFAP, which Dr. Karussis said has not been shown before, was observed in all 23 patients. Again, there was an additional reduction with repeated MSC treatments.
The safety and tolerability remained encouraging with longer follow-up. As in the original series, there were no serious adverse events. Headache and backache, which were more common among those receiving intrathecal injections of MSC in the original study, continued to be reported in the extension, but these were time-limited.
Although Dr. Karussis emphasized that these interim results await confirmation with longer follow-up and larger studies, he suggested that the consistency of benefit with early report provides “an additional hint of possible neuroprotective and neurotrophic effects.”
Mechanism of MSC Benefit Incompletely Documented
In patients with progressive MS, there is an urgent need for more and better therapies. MSCs, which reside primarily in bone marrow but can be found in other tissues, have been associated with immunomodulatory as well as neuroprotective effects in experimental studies, but whether one or the other or both of these activities are responsible for the clinical benefits observed so far is unresolved.
Others evaluating MSCs in the experimental setting have shown that these “produce a variety of soluble factors with immunomodulatory, neuroprotective, and repair-promoting properties,” said Jeffrey A. Cohen, MD, who was asked to comment on the findings. Dr. Cohen is director of the experimental therapeutics program at the Mellen Center for Multiple Sclerosis, Cleveland Clinic. He said that previous experimental work has encouraged clinical studies, including the work presented by Dr. Karussis.
While the late-breaker presentation provided data suggesting “persistent potent efficacy with good safety and tolerability,” Dr. Cohen pointed out that “the results from this group are substantially better than those reported by several other groups.” He called the difference in results “uncertain,” suggesting that more work is needed to prove that clinical benefit is reliably achieved.
“I think it is too early to tell if MSC transplantation is going to be useful. Other than [the data] reported by the Karussis group, the results have been rather disappointing,” Dr. Cohen said.
Dr. Karussis reports no potential conflicts of interest.
FROM ACTRIMS FORUM 2024
The Power of Patient-Reported Outcomes Is Inhibited by Multiple Barriers
WEST PALM BEACH, FLORIDA — , according to experts participating in a symposium at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
These barriers include a lack of consensus on how and which PROs to collect, lack of a systematic method of interpreting the meaning of PRO changes, and lack of reimbursement for the time to collect PRO data and enter it into the medical record, according to Robert McBurney, PhD, president of the nonprofit Accelerated Cure Project for Multiple Sclerosis, Washington.
Potentially Useful Clinical Information
PROs can identify hidden symptoms of MS as well as provide information on the relative importance of the standard measures of disease progression, such as disability, but at the current time “these are rarely captured or used in shared decision-making to guide treatment,” Dr. McBurney said.
A reasonable analogy can be made between MS and musculoskeletal diseases, such as arthritis, according to Dr. McBurney. In both, not all patients experience the burden of disease in the same way, whether measured with traditional laboratory or imaging evidence of disease activity or by PROs that capture anxiety, depression, and specific impairments affecting activities of daily living.
Yet, the Centers for Medicare and Medicaid Services (CMS) is now mandating the entry of PRO data for the reimbursement of some forms of orthopedic surgery, while MS is lagging behind, according to Dr. McBurney.
The difference between orthopedics and MS is evidence submitted to CMS showing that improvement in PROs matter for patient outcome and well-being. Dr. McBurney argued that the same type of data is lacking for MS.
More well-designed clinical trials are needed to confirm that beneficial effects on PROs can improve patient outcomes, but Dr. McBurney suggested that PRO data from the many MS patient registries might be an easier first step. He reported that 24 of 43 MS registries around the globe are now capturing PRO data.
Unfortunately, the AXON registry, which is managed by the American Academy of Neurology, is not one of them, Dr. McBurney said. This is not an oversight. Dr. McBurney explained that the first effort to add PROs to data collected by AXON was initiated more than 5 years ago, but several complications thwarted the process. A new effort has been recently scheduled.
By developing data showing that PROs matter, AAN “might lead the charge” for establishing the collection of PRO data as a standard of care and eliciting reimbursement from third-party payers for doing so, Dr. McBurney said. Nevertheless, he cautioned that validated methodology for collecting PRO data and identifying clinically meaningful changes in scores will be fundamental to PRO utility.
A Path Forward
In the best circumstance, PRO data captured at a patient visit would be analogous to a lab test. Just as blood tests generate data in the context of normative ranges for a dozen or more parameters, the PRO data could be displayed with the same type of context, allowing physicians and patients to see a specific PRO measure displayed against a normative range so results are easily interpreted, according to Dr. McBurney.
But, again, there are barriers. Numerous validated sets of PROs are available with no consensus on which might serve as a standard. While Dr. McBurney singled out the SymptoMScreen tool as one that is already recommended by the MS Data Alliance, a nonprofit organization supported by the European Charcot Foundation to transform real-world MS data into evidence suitable for MS care, he acknowledged it is just one of many options.
“The SymptoMScreen has been used in several clinical studies and it is relatively simple to use,” Dr. McBurney said. Even if there is no single “best” instrument for measuring PROs, a standard might move the process forward.
The president of the European Charcot Foundation, Giancarlo Comi, MD, agreed that PROs are almost certainly coming to the routine management of MS as each of the current barriers described by Dr. McBurney are addressed. He said that PROs are particularly important in managing progressive MS, for which he thinks that traditional biomarkers, such as brain images, are particularly poor at capturing the burden of disease.
“The EMA [European Medicines Agency] and the FDA [Food and Drug Administration] are both very interested in using PROs to evaluate treatments in MS,” he said.
PROs might be incorporated into routine care by clinicians convinced that they help in guiding treatment choices, but Dr. McBurney and Dr. Comi agreed that some approach, including financial incentives, to encourage clinicians to capture and record PROs is probably needed before they are used routinely.
Dr. McBurney reports no potential conflicts of interest. Dr. Comi reports financial relationships with Almirall, Celgene, Genzyme, Hoffman-LaRoche, Janssen, Merck, Novartis, and Sanofi.
WEST PALM BEACH, FLORIDA — , according to experts participating in a symposium at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
These barriers include a lack of consensus on how and which PROs to collect, lack of a systematic method of interpreting the meaning of PRO changes, and lack of reimbursement for the time to collect PRO data and enter it into the medical record, according to Robert McBurney, PhD, president of the nonprofit Accelerated Cure Project for Multiple Sclerosis, Washington.
Potentially Useful Clinical Information
PROs can identify hidden symptoms of MS as well as provide information on the relative importance of the standard measures of disease progression, such as disability, but at the current time “these are rarely captured or used in shared decision-making to guide treatment,” Dr. McBurney said.
A reasonable analogy can be made between MS and musculoskeletal diseases, such as arthritis, according to Dr. McBurney. In both, not all patients experience the burden of disease in the same way, whether measured with traditional laboratory or imaging evidence of disease activity or by PROs that capture anxiety, depression, and specific impairments affecting activities of daily living.
Yet, the Centers for Medicare and Medicaid Services (CMS) is now mandating the entry of PRO data for the reimbursement of some forms of orthopedic surgery, while MS is lagging behind, according to Dr. McBurney.
The difference between orthopedics and MS is evidence submitted to CMS showing that improvement in PROs matter for patient outcome and well-being. Dr. McBurney argued that the same type of data is lacking for MS.
More well-designed clinical trials are needed to confirm that beneficial effects on PROs can improve patient outcomes, but Dr. McBurney suggested that PRO data from the many MS patient registries might be an easier first step. He reported that 24 of 43 MS registries around the globe are now capturing PRO data.
Unfortunately, the AXON registry, which is managed by the American Academy of Neurology, is not one of them, Dr. McBurney said. This is not an oversight. Dr. McBurney explained that the first effort to add PROs to data collected by AXON was initiated more than 5 years ago, but several complications thwarted the process. A new effort has been recently scheduled.
By developing data showing that PROs matter, AAN “might lead the charge” for establishing the collection of PRO data as a standard of care and eliciting reimbursement from third-party payers for doing so, Dr. McBurney said. Nevertheless, he cautioned that validated methodology for collecting PRO data and identifying clinically meaningful changes in scores will be fundamental to PRO utility.
A Path Forward
In the best circumstance, PRO data captured at a patient visit would be analogous to a lab test. Just as blood tests generate data in the context of normative ranges for a dozen or more parameters, the PRO data could be displayed with the same type of context, allowing physicians and patients to see a specific PRO measure displayed against a normative range so results are easily interpreted, according to Dr. McBurney.
But, again, there are barriers. Numerous validated sets of PROs are available with no consensus on which might serve as a standard. While Dr. McBurney singled out the SymptoMScreen tool as one that is already recommended by the MS Data Alliance, a nonprofit organization supported by the European Charcot Foundation to transform real-world MS data into evidence suitable for MS care, he acknowledged it is just one of many options.
“The SymptoMScreen has been used in several clinical studies and it is relatively simple to use,” Dr. McBurney said. Even if there is no single “best” instrument for measuring PROs, a standard might move the process forward.
The president of the European Charcot Foundation, Giancarlo Comi, MD, agreed that PROs are almost certainly coming to the routine management of MS as each of the current barriers described by Dr. McBurney are addressed. He said that PROs are particularly important in managing progressive MS, for which he thinks that traditional biomarkers, such as brain images, are particularly poor at capturing the burden of disease.
“The EMA [European Medicines Agency] and the FDA [Food and Drug Administration] are both very interested in using PROs to evaluate treatments in MS,” he said.
PROs might be incorporated into routine care by clinicians convinced that they help in guiding treatment choices, but Dr. McBurney and Dr. Comi agreed that some approach, including financial incentives, to encourage clinicians to capture and record PROs is probably needed before they are used routinely.
Dr. McBurney reports no potential conflicts of interest. Dr. Comi reports financial relationships with Almirall, Celgene, Genzyme, Hoffman-LaRoche, Janssen, Merck, Novartis, and Sanofi.
WEST PALM BEACH, FLORIDA — , according to experts participating in a symposium at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
These barriers include a lack of consensus on how and which PROs to collect, lack of a systematic method of interpreting the meaning of PRO changes, and lack of reimbursement for the time to collect PRO data and enter it into the medical record, according to Robert McBurney, PhD, president of the nonprofit Accelerated Cure Project for Multiple Sclerosis, Washington.
Potentially Useful Clinical Information
PROs can identify hidden symptoms of MS as well as provide information on the relative importance of the standard measures of disease progression, such as disability, but at the current time “these are rarely captured or used in shared decision-making to guide treatment,” Dr. McBurney said.
A reasonable analogy can be made between MS and musculoskeletal diseases, such as arthritis, according to Dr. McBurney. In both, not all patients experience the burden of disease in the same way, whether measured with traditional laboratory or imaging evidence of disease activity or by PROs that capture anxiety, depression, and specific impairments affecting activities of daily living.
Yet, the Centers for Medicare and Medicaid Services (CMS) is now mandating the entry of PRO data for the reimbursement of some forms of orthopedic surgery, while MS is lagging behind, according to Dr. McBurney.
The difference between orthopedics and MS is evidence submitted to CMS showing that improvement in PROs matter for patient outcome and well-being. Dr. McBurney argued that the same type of data is lacking for MS.
More well-designed clinical trials are needed to confirm that beneficial effects on PROs can improve patient outcomes, but Dr. McBurney suggested that PRO data from the many MS patient registries might be an easier first step. He reported that 24 of 43 MS registries around the globe are now capturing PRO data.
Unfortunately, the AXON registry, which is managed by the American Academy of Neurology, is not one of them, Dr. McBurney said. This is not an oversight. Dr. McBurney explained that the first effort to add PROs to data collected by AXON was initiated more than 5 years ago, but several complications thwarted the process. A new effort has been recently scheduled.
By developing data showing that PROs matter, AAN “might lead the charge” for establishing the collection of PRO data as a standard of care and eliciting reimbursement from third-party payers for doing so, Dr. McBurney said. Nevertheless, he cautioned that validated methodology for collecting PRO data and identifying clinically meaningful changes in scores will be fundamental to PRO utility.
A Path Forward
In the best circumstance, PRO data captured at a patient visit would be analogous to a lab test. Just as blood tests generate data in the context of normative ranges for a dozen or more parameters, the PRO data could be displayed with the same type of context, allowing physicians and patients to see a specific PRO measure displayed against a normative range so results are easily interpreted, according to Dr. McBurney.
But, again, there are barriers. Numerous validated sets of PROs are available with no consensus on which might serve as a standard. While Dr. McBurney singled out the SymptoMScreen tool as one that is already recommended by the MS Data Alliance, a nonprofit organization supported by the European Charcot Foundation to transform real-world MS data into evidence suitable for MS care, he acknowledged it is just one of many options.
“The SymptoMScreen has been used in several clinical studies and it is relatively simple to use,” Dr. McBurney said. Even if there is no single “best” instrument for measuring PROs, a standard might move the process forward.
The president of the European Charcot Foundation, Giancarlo Comi, MD, agreed that PROs are almost certainly coming to the routine management of MS as each of the current barriers described by Dr. McBurney are addressed. He said that PROs are particularly important in managing progressive MS, for which he thinks that traditional biomarkers, such as brain images, are particularly poor at capturing the burden of disease.
“The EMA [European Medicines Agency] and the FDA [Food and Drug Administration] are both very interested in using PROs to evaluate treatments in MS,” he said.
PROs might be incorporated into routine care by clinicians convinced that they help in guiding treatment choices, but Dr. McBurney and Dr. Comi agreed that some approach, including financial incentives, to encourage clinicians to capture and record PROs is probably needed before they are used routinely.
Dr. McBurney reports no potential conflicts of interest. Dr. Comi reports financial relationships with Almirall, Celgene, Genzyme, Hoffman-LaRoche, Janssen, Merck, Novartis, and Sanofi.
FROM ACTRIMS FORUM 2024
Randomized Trial Confirms Prognostic Value of Neurofilament Light Chains in MS
WEST PALM BEACH, FLORIDA — regardless of treatment assignment, according to new substudy data from the ASCLEPIOS I/II trials presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
There are numerous studies supporting sNfL as a prognostic biomarker in MS, but a series of preplanned ASCLEPIOS substudies provided an opportunity to evaluate its predictive value across different therapies, according to Thomas P. Leist, MD, PhD, division chief, Multiple Sclerosis/Neuroimmunology, Thomas Jefferson University, Philadelphia, Pennsylvania.
These data “support the use of a single sNfL threshold to prognosticate disease activity in patients with relapsing-remitting MS on a disease-modifying therapy,” Dr. Leist reported.
When those with elevated sNfL levels, defined as being above the median (≥ 9.3 pg/mL), at 3 months were compared with those with lower sNfL levels (< 9.3 pg/mL), the on-treatment annualized rate of new or enlarging T2 lesions was 2.2-fold (P < .001) greater. When measured at 12 months, the annualized rate was 3.6-fold greater (P < .001).
These differences in annualized rates for higher sNfL levels at 3 months (3.67 vs 1.69) and 12 months (4.90 vs 1.37) were independent of assigned therapy.
The ASCLEPIOS I/II trials compared the injectable anti-CD20 monoclonal antibody ofatumumab to teriflunomide, an oral inhibitor of pyrimidine synthesis, using a double-dummy, double-blind protocol. In the two trials that were published together (N Engl J Med. 2020 Aug 6;383[6]:546-557. doi: 10.1056/NEJMoa1917246), the annualized relapse rate was about 50% lower for ofatumumab (P < .001 in both trials). Other markers of activity, such as new lesions on T1- and T2-weighted imaging as well as sNfL levels, all favored ofatumumab numerically even if not all the secondary measures reached statistical significance.
Is sNfL Relevant Independent of Treatment?
In this preplanned substudy, the question was whether sNfL levels over the course of early follow-up were prognostic regardless of treatment assignment. This was not only shown for the study population overall but for several important subpopulations, such as those defined by race and ethnicity and body mass index (BMI). Of the 1892 patients enrolled in the two ASCLEPIOS trials, baseline sNfL data collection, which was part of the study protocol, was available for 1746 (92.8%).
Nearly 90% of the patients enrolled in the ASCLEPIOS trials were White with the remainder nearly evenly split between Black, Asian, and other, a category that included unknown race. In all groups, the annualized mean rate of new or enlarging T2 lesions was more than double among those with a sNfL above the mean versus those below the mean.
While these results were based on an above-or-below mean sNfL threshold, “future work should evaluate how this single sNfL threshold could be optimized with a specific target and population in mind,” according to the lead investigator on this analysis, Silvia R. Delgado, MD, a professor in the Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida.
The BMI analysis also supported the same idea. Anne H. Cross, MD, Washington University School of Medicine, St. Louis, Missouri, who led this work, concluded that a single sNfL threshold was prognostic for all groups studied, “including those defined by BMI and age.”
Optimal sNfL Threshold May Not Be Defined
Like Dr. Leist, Dr. Cross emphasized that while these data suggest that sNfL is a useful prognostic indicator in patients on treatment regardless of the treatment they are receiving, these subanalyses “support further work on the optimization of sNfL.” The potential for a more clinically useful threshold to define elevated sNfL has not been ruled out.
Although Daniel Ontaneda, MD, PhD, an associate professor of neurology, Cleveland Clinic, Cleveland, Ohio, did not review these data in detail, he agreed that evidence showing sNfL levels to be consistently prognostic regardless of background therapy is potentially important new information. Dr. Ontaneda, the chair of this year’s ACTRIMS conference, said that progress in defining new biomarkers for RRMS, such as sNfL, is needed and potentially clinically meaningful.
However, asked if evaluating sNfL after a specific time on therapy, such as 3 months, would be helpful to clinicians guiding therapy, Dr. Ontaneda said, “This is a different question.” He said a separate set of studies will be needed to confirm that acting on sNfL levels can improve outcomes.
Dr. Leist reported financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Janssen, Sanofi, and Novartis, which was the sponsor of the ASCLEPIOS trials. Dr. Salvado has financial relationships with EMD Serono and Novartis. Dr. Cross has financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Horizon, Novartis, Octave, and TG Therapeutics. Dr. Ontaneda reports no potential conflicts of interest.
WEST PALM BEACH, FLORIDA — regardless of treatment assignment, according to new substudy data from the ASCLEPIOS I/II trials presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
There are numerous studies supporting sNfL as a prognostic biomarker in MS, but a series of preplanned ASCLEPIOS substudies provided an opportunity to evaluate its predictive value across different therapies, according to Thomas P. Leist, MD, PhD, division chief, Multiple Sclerosis/Neuroimmunology, Thomas Jefferson University, Philadelphia, Pennsylvania.
These data “support the use of a single sNfL threshold to prognosticate disease activity in patients with relapsing-remitting MS on a disease-modifying therapy,” Dr. Leist reported.
When those with elevated sNfL levels, defined as being above the median (≥ 9.3 pg/mL), at 3 months were compared with those with lower sNfL levels (< 9.3 pg/mL), the on-treatment annualized rate of new or enlarging T2 lesions was 2.2-fold (P < .001) greater. When measured at 12 months, the annualized rate was 3.6-fold greater (P < .001).
These differences in annualized rates for higher sNfL levels at 3 months (3.67 vs 1.69) and 12 months (4.90 vs 1.37) were independent of assigned therapy.
The ASCLEPIOS I/II trials compared the injectable anti-CD20 monoclonal antibody ofatumumab to teriflunomide, an oral inhibitor of pyrimidine synthesis, using a double-dummy, double-blind protocol. In the two trials that were published together (N Engl J Med. 2020 Aug 6;383[6]:546-557. doi: 10.1056/NEJMoa1917246), the annualized relapse rate was about 50% lower for ofatumumab (P < .001 in both trials). Other markers of activity, such as new lesions on T1- and T2-weighted imaging as well as sNfL levels, all favored ofatumumab numerically even if not all the secondary measures reached statistical significance.
Is sNfL Relevant Independent of Treatment?
In this preplanned substudy, the question was whether sNfL levels over the course of early follow-up were prognostic regardless of treatment assignment. This was not only shown for the study population overall but for several important subpopulations, such as those defined by race and ethnicity and body mass index (BMI). Of the 1892 patients enrolled in the two ASCLEPIOS trials, baseline sNfL data collection, which was part of the study protocol, was available for 1746 (92.8%).
Nearly 90% of the patients enrolled in the ASCLEPIOS trials were White with the remainder nearly evenly split between Black, Asian, and other, a category that included unknown race. In all groups, the annualized mean rate of new or enlarging T2 lesions was more than double among those with a sNfL above the mean versus those below the mean.
While these results were based on an above-or-below mean sNfL threshold, “future work should evaluate how this single sNfL threshold could be optimized with a specific target and population in mind,” according to the lead investigator on this analysis, Silvia R. Delgado, MD, a professor in the Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida.
The BMI analysis also supported the same idea. Anne H. Cross, MD, Washington University School of Medicine, St. Louis, Missouri, who led this work, concluded that a single sNfL threshold was prognostic for all groups studied, “including those defined by BMI and age.”
Optimal sNfL Threshold May Not Be Defined
Like Dr. Leist, Dr. Cross emphasized that while these data suggest that sNfL is a useful prognostic indicator in patients on treatment regardless of the treatment they are receiving, these subanalyses “support further work on the optimization of sNfL.” The potential for a more clinically useful threshold to define elevated sNfL has not been ruled out.
Although Daniel Ontaneda, MD, PhD, an associate professor of neurology, Cleveland Clinic, Cleveland, Ohio, did not review these data in detail, he agreed that evidence showing sNfL levels to be consistently prognostic regardless of background therapy is potentially important new information. Dr. Ontaneda, the chair of this year’s ACTRIMS conference, said that progress in defining new biomarkers for RRMS, such as sNfL, is needed and potentially clinically meaningful.
However, asked if evaluating sNfL after a specific time on therapy, such as 3 months, would be helpful to clinicians guiding therapy, Dr. Ontaneda said, “This is a different question.” He said a separate set of studies will be needed to confirm that acting on sNfL levels can improve outcomes.
Dr. Leist reported financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Janssen, Sanofi, and Novartis, which was the sponsor of the ASCLEPIOS trials. Dr. Salvado has financial relationships with EMD Serono and Novartis. Dr. Cross has financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Horizon, Novartis, Octave, and TG Therapeutics. Dr. Ontaneda reports no potential conflicts of interest.
WEST PALM BEACH, FLORIDA — regardless of treatment assignment, according to new substudy data from the ASCLEPIOS I/II trials presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
There are numerous studies supporting sNfL as a prognostic biomarker in MS, but a series of preplanned ASCLEPIOS substudies provided an opportunity to evaluate its predictive value across different therapies, according to Thomas P. Leist, MD, PhD, division chief, Multiple Sclerosis/Neuroimmunology, Thomas Jefferson University, Philadelphia, Pennsylvania.
These data “support the use of a single sNfL threshold to prognosticate disease activity in patients with relapsing-remitting MS on a disease-modifying therapy,” Dr. Leist reported.
When those with elevated sNfL levels, defined as being above the median (≥ 9.3 pg/mL), at 3 months were compared with those with lower sNfL levels (< 9.3 pg/mL), the on-treatment annualized rate of new or enlarging T2 lesions was 2.2-fold (P < .001) greater. When measured at 12 months, the annualized rate was 3.6-fold greater (P < .001).
These differences in annualized rates for higher sNfL levels at 3 months (3.67 vs 1.69) and 12 months (4.90 vs 1.37) were independent of assigned therapy.
The ASCLEPIOS I/II trials compared the injectable anti-CD20 monoclonal antibody ofatumumab to teriflunomide, an oral inhibitor of pyrimidine synthesis, using a double-dummy, double-blind protocol. In the two trials that were published together (N Engl J Med. 2020 Aug 6;383[6]:546-557. doi: 10.1056/NEJMoa1917246), the annualized relapse rate was about 50% lower for ofatumumab (P < .001 in both trials). Other markers of activity, such as new lesions on T1- and T2-weighted imaging as well as sNfL levels, all favored ofatumumab numerically even if not all the secondary measures reached statistical significance.
Is sNfL Relevant Independent of Treatment?
In this preplanned substudy, the question was whether sNfL levels over the course of early follow-up were prognostic regardless of treatment assignment. This was not only shown for the study population overall but for several important subpopulations, such as those defined by race and ethnicity and body mass index (BMI). Of the 1892 patients enrolled in the two ASCLEPIOS trials, baseline sNfL data collection, which was part of the study protocol, was available for 1746 (92.8%).
Nearly 90% of the patients enrolled in the ASCLEPIOS trials were White with the remainder nearly evenly split between Black, Asian, and other, a category that included unknown race. In all groups, the annualized mean rate of new or enlarging T2 lesions was more than double among those with a sNfL above the mean versus those below the mean.
While these results were based on an above-or-below mean sNfL threshold, “future work should evaluate how this single sNfL threshold could be optimized with a specific target and population in mind,” according to the lead investigator on this analysis, Silvia R. Delgado, MD, a professor in the Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida.
The BMI analysis also supported the same idea. Anne H. Cross, MD, Washington University School of Medicine, St. Louis, Missouri, who led this work, concluded that a single sNfL threshold was prognostic for all groups studied, “including those defined by BMI and age.”
Optimal sNfL Threshold May Not Be Defined
Like Dr. Leist, Dr. Cross emphasized that while these data suggest that sNfL is a useful prognostic indicator in patients on treatment regardless of the treatment they are receiving, these subanalyses “support further work on the optimization of sNfL.” The potential for a more clinically useful threshold to define elevated sNfL has not been ruled out.
Although Daniel Ontaneda, MD, PhD, an associate professor of neurology, Cleveland Clinic, Cleveland, Ohio, did not review these data in detail, he agreed that evidence showing sNfL levels to be consistently prognostic regardless of background therapy is potentially important new information. Dr. Ontaneda, the chair of this year’s ACTRIMS conference, said that progress in defining new biomarkers for RRMS, such as sNfL, is needed and potentially clinically meaningful.
However, asked if evaluating sNfL after a specific time on therapy, such as 3 months, would be helpful to clinicians guiding therapy, Dr. Ontaneda said, “This is a different question.” He said a separate set of studies will be needed to confirm that acting on sNfL levels can improve outcomes.
Dr. Leist reported financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Janssen, Sanofi, and Novartis, which was the sponsor of the ASCLEPIOS trials. Dr. Salvado has financial relationships with EMD Serono and Novartis. Dr. Cross has financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Horizon, Novartis, Octave, and TG Therapeutics. Dr. Ontaneda reports no potential conflicts of interest.
FROM ACTRIMS FORUM 2024
Frexalimab Promising for Relapsing Multiple Sclerosis
At week 12, there was an 89% reduction in new gadolinium (Gd)-enhancing T1 brain lesions — a standard measure of active inflammation in MS – in the high-dose frexalimab group and a 79% reduction in the low-dose treatment group compared with placebo, meeting the study’s primary endpoint.
The effects of frexalimab were sustained over time, “especially at the high dose of frexalimab where 96% of patients were free of new active lesions after 24 weeks of treatment,” first author Patrick Vermersch, MD, PhD, University of Lille, CHU Lille, France, said in a news release.
The full results were published online on in The New England Journal of Medicine, following presentation of preliminary data at the Consortium of Multiple Sclerosis Centers 2023 Annual Meeting.
‘Unambiguous Benefit’
Frexalimab blocks the costimulatory CD40/CD40L pathway, which regulates both adaptive and innate immune responses, and has been implicated in the pathogenesis of MS.
“Through this unique upstream mechanism of action, frexalimab has the potential to address both acute and chronic neuroinflammation in MS, without causing lymphocyte depletion,” a Sanofi press statement noted.
The phase 2 study enrolled 129 adults (mean age, 36 years; 66% women) with relapsing MS, 30% of whom had Gd-enhancing lesions at baseline.
Participants received 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose; n = 52), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose; n = 51), or matching placebos for each active treatment (n = 12 and n = 14, respectively).
All but four patients completed the 12-week double-blind period and entered the open-label period.
The primary end point was the number of new Gd-enhancing T1-weighted lesions seen on MRI at week 12 relative to week 8.
At week 12, the adjusted mean number of new Gd-enhancing T1 lesions was 0.2 and 0.3 in the high- and low-dose frexalimab groups, respectively, compared with 1.4 in the pooled placebo group.
The rate ratios, as compared with placebo, were 0.11 in the high-dose group and 0.21 in the low-dose group, corresponding to 89% and 79% reductions in the high- and low-dose groups, respectively.
On the secondary endpoint of number of new/enlarging T2-weighted lesions at week 12, rate ratios in the high- and low-dose groups were 0.08 and 0.14, respectively, corresponding to 92% and 86% reduction in the high- and low-dose treatment groups vs placebo.
The effects were sustained over time across both active treatment groups.
Frexalimab also lowered plasma levels of neurofilament light chain, a biomarker of neuroaxonal damage in MS, as well as plasma levels of CXCL13, a biomarker of inflammatory activity.
Phase 3 Trials Underway
The authors noted that the trial was too brief and small to draw conclusions regarding clinical outcomes. However, during the 12-week double-blind period, no relapses occurred in the high-dose frexalimab group, whereas relapses occurred in roughly 4% of those in the low-dose frexalimab group and the pooled placebo group.
There was no change from baseline to 12 weeks in median scores on the Expanded Disability Status Scale in any study group.
No serious or severe adverse events or deaths were reported during the double-blind period. There were no thromboembolic events — a concern with first-generation anti–CD40L antibodies.
Depletion of lymphocytes was not observed. More infections were observed with frexalimab than with placebo, but no serious infections occurred during 24 weeks of frexalimab treatment. The most common adverse events were COVID-19 and headache. All cases of COVID-19 were uncomplicated and mild to moderate in severity.
Bolstered by the promising phase 2 data, Sanofi has initiated two phase 3 studies assessing frexalimab in relapsing MS and non-relapsing secondary progressive MS.
‘A High Bar for Any New Treatment’
In an accompanying editorial, Stephen L. Hauser, MD, with UCSF Weill Institute for Neurosciences, San Francisco, California, wrote that the results “appear clear, although the clinical significance is uncertain — clear because there was an unambiguous benefit with regard to short-term MRI outcomes in patients who received frexalimab as compared with those who received placebo and because a generally low level of MRI activity persisted during an additional 12-week open-label extension period.”
If the findings hold with longer-term use, Dr. Hauser continued, “it seems likely that there will be a protective effect of frexalimab therapy with regard to relapses of multiple sclerosis.”
Dr. Hauser noted, however, that the “striking clinical benefits and safety profile of the available high-efficacy therapies for relapsing multiple sclerosis create a high bar for any new treatment.”
“In this trial, the MRI outcomes with frexalimab therapy were impressive but appear to be less complete than those with anti-CD20 agents, although trials of different agents cannot be directly compared.”
“Even if future studies show frexalimab to be competitive with currently available therapies for relapsing multiple sclerosis, the paramount need is for more effective therapy against progression,” Dr. Hauser wrote.
While the current trial was neither designed nor powered to assess benefits against progressive MS, “progression is where the true clinical value of frexalimab, and its place in the therapeutic armamentarium against multiple sclerosis, will need to be defined,” Dr. Hauser concluded.
The study was supported by Sanofi. Disclosures for authors and editorialist are available at NEJM.org.
A version of this article first appeared on Medscape.com.
At week 12, there was an 89% reduction in new gadolinium (Gd)-enhancing T1 brain lesions — a standard measure of active inflammation in MS – in the high-dose frexalimab group and a 79% reduction in the low-dose treatment group compared with placebo, meeting the study’s primary endpoint.
The effects of frexalimab were sustained over time, “especially at the high dose of frexalimab where 96% of patients were free of new active lesions after 24 weeks of treatment,” first author Patrick Vermersch, MD, PhD, University of Lille, CHU Lille, France, said in a news release.
The full results were published online on in The New England Journal of Medicine, following presentation of preliminary data at the Consortium of Multiple Sclerosis Centers 2023 Annual Meeting.
‘Unambiguous Benefit’
Frexalimab blocks the costimulatory CD40/CD40L pathway, which regulates both adaptive and innate immune responses, and has been implicated in the pathogenesis of MS.
“Through this unique upstream mechanism of action, frexalimab has the potential to address both acute and chronic neuroinflammation in MS, without causing lymphocyte depletion,” a Sanofi press statement noted.
The phase 2 study enrolled 129 adults (mean age, 36 years; 66% women) with relapsing MS, 30% of whom had Gd-enhancing lesions at baseline.
Participants received 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose; n = 52), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose; n = 51), or matching placebos for each active treatment (n = 12 and n = 14, respectively).
All but four patients completed the 12-week double-blind period and entered the open-label period.
The primary end point was the number of new Gd-enhancing T1-weighted lesions seen on MRI at week 12 relative to week 8.
At week 12, the adjusted mean number of new Gd-enhancing T1 lesions was 0.2 and 0.3 in the high- and low-dose frexalimab groups, respectively, compared with 1.4 in the pooled placebo group.
The rate ratios, as compared with placebo, were 0.11 in the high-dose group and 0.21 in the low-dose group, corresponding to 89% and 79% reductions in the high- and low-dose groups, respectively.
On the secondary endpoint of number of new/enlarging T2-weighted lesions at week 12, rate ratios in the high- and low-dose groups were 0.08 and 0.14, respectively, corresponding to 92% and 86% reduction in the high- and low-dose treatment groups vs placebo.
The effects were sustained over time across both active treatment groups.
Frexalimab also lowered plasma levels of neurofilament light chain, a biomarker of neuroaxonal damage in MS, as well as plasma levels of CXCL13, a biomarker of inflammatory activity.
Phase 3 Trials Underway
The authors noted that the trial was too brief and small to draw conclusions regarding clinical outcomes. However, during the 12-week double-blind period, no relapses occurred in the high-dose frexalimab group, whereas relapses occurred in roughly 4% of those in the low-dose frexalimab group and the pooled placebo group.
There was no change from baseline to 12 weeks in median scores on the Expanded Disability Status Scale in any study group.
No serious or severe adverse events or deaths were reported during the double-blind period. There were no thromboembolic events — a concern with first-generation anti–CD40L antibodies.
Depletion of lymphocytes was not observed. More infections were observed with frexalimab than with placebo, but no serious infections occurred during 24 weeks of frexalimab treatment. The most common adverse events were COVID-19 and headache. All cases of COVID-19 were uncomplicated and mild to moderate in severity.
Bolstered by the promising phase 2 data, Sanofi has initiated two phase 3 studies assessing frexalimab in relapsing MS and non-relapsing secondary progressive MS.
‘A High Bar for Any New Treatment’
In an accompanying editorial, Stephen L. Hauser, MD, with UCSF Weill Institute for Neurosciences, San Francisco, California, wrote that the results “appear clear, although the clinical significance is uncertain — clear because there was an unambiguous benefit with regard to short-term MRI outcomes in patients who received frexalimab as compared with those who received placebo and because a generally low level of MRI activity persisted during an additional 12-week open-label extension period.”
If the findings hold with longer-term use, Dr. Hauser continued, “it seems likely that there will be a protective effect of frexalimab therapy with regard to relapses of multiple sclerosis.”
Dr. Hauser noted, however, that the “striking clinical benefits and safety profile of the available high-efficacy therapies for relapsing multiple sclerosis create a high bar for any new treatment.”
“In this trial, the MRI outcomes with frexalimab therapy were impressive but appear to be less complete than those with anti-CD20 agents, although trials of different agents cannot be directly compared.”
“Even if future studies show frexalimab to be competitive with currently available therapies for relapsing multiple sclerosis, the paramount need is for more effective therapy against progression,” Dr. Hauser wrote.
While the current trial was neither designed nor powered to assess benefits against progressive MS, “progression is where the true clinical value of frexalimab, and its place in the therapeutic armamentarium against multiple sclerosis, will need to be defined,” Dr. Hauser concluded.
The study was supported by Sanofi. Disclosures for authors and editorialist are available at NEJM.org.
A version of this article first appeared on Medscape.com.
At week 12, there was an 89% reduction in new gadolinium (Gd)-enhancing T1 brain lesions — a standard measure of active inflammation in MS – in the high-dose frexalimab group and a 79% reduction in the low-dose treatment group compared with placebo, meeting the study’s primary endpoint.
The effects of frexalimab were sustained over time, “especially at the high dose of frexalimab where 96% of patients were free of new active lesions after 24 weeks of treatment,” first author Patrick Vermersch, MD, PhD, University of Lille, CHU Lille, France, said in a news release.
The full results were published online on in The New England Journal of Medicine, following presentation of preliminary data at the Consortium of Multiple Sclerosis Centers 2023 Annual Meeting.
‘Unambiguous Benefit’
Frexalimab blocks the costimulatory CD40/CD40L pathway, which regulates both adaptive and innate immune responses, and has been implicated in the pathogenesis of MS.
“Through this unique upstream mechanism of action, frexalimab has the potential to address both acute and chronic neuroinflammation in MS, without causing lymphocyte depletion,” a Sanofi press statement noted.
The phase 2 study enrolled 129 adults (mean age, 36 years; 66% women) with relapsing MS, 30% of whom had Gd-enhancing lesions at baseline.
Participants received 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose; n = 52), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose; n = 51), or matching placebos for each active treatment (n = 12 and n = 14, respectively).
All but four patients completed the 12-week double-blind period and entered the open-label period.
The primary end point was the number of new Gd-enhancing T1-weighted lesions seen on MRI at week 12 relative to week 8.
At week 12, the adjusted mean number of new Gd-enhancing T1 lesions was 0.2 and 0.3 in the high- and low-dose frexalimab groups, respectively, compared with 1.4 in the pooled placebo group.
The rate ratios, as compared with placebo, were 0.11 in the high-dose group and 0.21 in the low-dose group, corresponding to 89% and 79% reductions in the high- and low-dose groups, respectively.
On the secondary endpoint of number of new/enlarging T2-weighted lesions at week 12, rate ratios in the high- and low-dose groups were 0.08 and 0.14, respectively, corresponding to 92% and 86% reduction in the high- and low-dose treatment groups vs placebo.
The effects were sustained over time across both active treatment groups.
Frexalimab also lowered plasma levels of neurofilament light chain, a biomarker of neuroaxonal damage in MS, as well as plasma levels of CXCL13, a biomarker of inflammatory activity.
Phase 3 Trials Underway
The authors noted that the trial was too brief and small to draw conclusions regarding clinical outcomes. However, during the 12-week double-blind period, no relapses occurred in the high-dose frexalimab group, whereas relapses occurred in roughly 4% of those in the low-dose frexalimab group and the pooled placebo group.
There was no change from baseline to 12 weeks in median scores on the Expanded Disability Status Scale in any study group.
No serious or severe adverse events or deaths were reported during the double-blind period. There were no thromboembolic events — a concern with first-generation anti–CD40L antibodies.
Depletion of lymphocytes was not observed. More infections were observed with frexalimab than with placebo, but no serious infections occurred during 24 weeks of frexalimab treatment. The most common adverse events were COVID-19 and headache. All cases of COVID-19 were uncomplicated and mild to moderate in severity.
Bolstered by the promising phase 2 data, Sanofi has initiated two phase 3 studies assessing frexalimab in relapsing MS and non-relapsing secondary progressive MS.
‘A High Bar for Any New Treatment’
In an accompanying editorial, Stephen L. Hauser, MD, with UCSF Weill Institute for Neurosciences, San Francisco, California, wrote that the results “appear clear, although the clinical significance is uncertain — clear because there was an unambiguous benefit with regard to short-term MRI outcomes in patients who received frexalimab as compared with those who received placebo and because a generally low level of MRI activity persisted during an additional 12-week open-label extension period.”
If the findings hold with longer-term use, Dr. Hauser continued, “it seems likely that there will be a protective effect of frexalimab therapy with regard to relapses of multiple sclerosis.”
Dr. Hauser noted, however, that the “striking clinical benefits and safety profile of the available high-efficacy therapies for relapsing multiple sclerosis create a high bar for any new treatment.”
“In this trial, the MRI outcomes with frexalimab therapy were impressive but appear to be less complete than those with anti-CD20 agents, although trials of different agents cannot be directly compared.”
“Even if future studies show frexalimab to be competitive with currently available therapies for relapsing multiple sclerosis, the paramount need is for more effective therapy against progression,” Dr. Hauser wrote.
While the current trial was neither designed nor powered to assess benefits against progressive MS, “progression is where the true clinical value of frexalimab, and its place in the therapeutic armamentarium against multiple sclerosis, will need to be defined,” Dr. Hauser concluded.
The study was supported by Sanofi. Disclosures for authors and editorialist are available at NEJM.org.
A version of this article first appeared on Medscape.com.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Barriers to Remyelinating Drugs in MS Are Falling as Science Advances
WEST PALM BEACH, FLORIDA — , according to a summary of the science as well as a late-breaker study presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
In an outline of barriers to remyelinating drugs, including the challenge of delivering well-tolerated therapies into the central nervous system (CNS), Ari J. Green, MD, Chief of the Division of Neuroimmunology and Glial Biology, University of California, San Francisco, spoke specifically about recent progress in drug development.
“The important thing is that once we understand the biology, we can turn barriers into opportunities,” he said as he outlined advances over the 6 years since he led the ReBUILD trial.
“We are thinking of remyelination therapies as something off in the horizon,” said Dr. Green, but “the horizon might be closer than we might imagine.”
The double-blind ReBUILD trial provided the first evidence of activity from a remyelinating drug. In this study, 50 patients with chronic demyelinating optic neuropathy and relapsing-remitting MS were randomized to twice daily doses (5-36 mg) of clemastine fumarate for 90 days followed by placebo for 60 days or to placebo for 60 days followed by active drug for 90 days.
Remyelinating Effect Documented at Multiple Sites
The improvement on the primary endpoint of visual evoked potentials was interpreted as evidence that the therapy had a positive remyelinating effect, and Dr. Green said that the result has been reproduced by more than a dozen other centers.
The theoretical benefit is from a favorable effect on myelin-producing stem cells, but Dr. Green emphasized that theoretical benefits are not enough for moving the field forward. Negative trials with a theoretical potential to generate remyelination both preceded and followed ReBUILD. Examples include the RENEW study with the anti-lingo monoclonal antibody opicinumab and the CCMR One study with the non-selective retinoid X receptor agonist bexarotene.
Whether there is benefit or failure, “we need to be able to tell what is going on,” Dr. Green said. The reason is that a negative result is not necessarily due to the absence of a meaningful remyelination. Rather, other variables, such as an insufficient number of axons to remyelinate, might explain a lack of effect.
Citing evidence that remyelination and demyelination are often concurrent events, Dr. Green said that there is an urgent need for tools to objectively quantify myelination in order to document that drugs purported to favorably influence myelin repair are doing so. Surrogate markers are potentially unreliable.
“There is an unfortunate tendency in our field to overinterpret atrophy and neurodegeneration and to use those terms too loosely,” Dr. Green said. He said these terms are not interchangeable.
One basis for excitement is the growing support for the theory that oligodendrocyte progenitor cell (OPC) recruitment is critical to the remyelination process. By activating these cells or blocking inhibitors of their activity, experimental evidence suggests new myelin formation can occur. However, a clinically meaningful benefit might still be dependent on multiple additional factors, including the timing of OPC recruitment, Dr. Green explained.
“We might need to provide drugs with a remyelinating effect very early in the process,” he said.
The progress in understanding the interacting factors that define the biology of remyelination is the basis for new enthusiasm about this field, agreed Véronique Miron, PhD, Chair of the Multiple Sclerosis Research, Barlo MS Center, Toronto. Dr. Miron, professor in the Department of Immunology at the University of Toronto, identified the session on remyelination in which Dr. Green spoke as one of the highlights of this year’s ACTRIMS conference.
Late-breaker: Two Remyelinating Drugs with Promise
Consistent with this progress, a late-breaker presentation on two drugs that promote oligodendrocyte formation and remyelination in the experimental setting reinforced the growing array of potential therapeutic targets to generate remyelination. The two drugs, CVL-1001 and CVL-2001, act by inhibiting the cholesterol biosynthesis enzymes sterol 14-demethylase (CYP51) and an emopamil binding protein (EBP).
Multiple studies have suggested that CYP51 and EBP are “key therapeutic targets to promote oligodendrocyte formation,” thereby promoting remyelination, reported Brad T. Lang, PhD, vice president of research for Convelo Therapeutics, Cleveland.
The drugs performed as predicted in animal models, where remyelination was documented, and in promoting human oligodendrocyte formation in human brain organoids. The development of these agents has been accompanied by strategy to measure their activity.
“We established a mechanistic biomarker to assess target engagement in the CNS and periphery to guide the next steps in preclinical and clinical development,” Dr. Lang said.
He called these drugs “first-in-class potential therapies in the field of remyelination.” While he acknowledged that no clinical studies have yet been performed, his late-breaker presentation indicated that many of the criteria identified by Dr. Green, including an ability to penetrate the CNS and a plausible, measurable mechanism of action have been fulfilled.
Dr. Green reported financial relationships with Biogen, Mylan, and Novartis. Dr. Miron reported no potential conflicts of interest.
WEST PALM BEACH, FLORIDA — , according to a summary of the science as well as a late-breaker study presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
In an outline of barriers to remyelinating drugs, including the challenge of delivering well-tolerated therapies into the central nervous system (CNS), Ari J. Green, MD, Chief of the Division of Neuroimmunology and Glial Biology, University of California, San Francisco, spoke specifically about recent progress in drug development.
“The important thing is that once we understand the biology, we can turn barriers into opportunities,” he said as he outlined advances over the 6 years since he led the ReBUILD trial.
“We are thinking of remyelination therapies as something off in the horizon,” said Dr. Green, but “the horizon might be closer than we might imagine.”
The double-blind ReBUILD trial provided the first evidence of activity from a remyelinating drug. In this study, 50 patients with chronic demyelinating optic neuropathy and relapsing-remitting MS were randomized to twice daily doses (5-36 mg) of clemastine fumarate for 90 days followed by placebo for 60 days or to placebo for 60 days followed by active drug for 90 days.
Remyelinating Effect Documented at Multiple Sites
The improvement on the primary endpoint of visual evoked potentials was interpreted as evidence that the therapy had a positive remyelinating effect, and Dr. Green said that the result has been reproduced by more than a dozen other centers.
The theoretical benefit is from a favorable effect on myelin-producing stem cells, but Dr. Green emphasized that theoretical benefits are not enough for moving the field forward. Negative trials with a theoretical potential to generate remyelination both preceded and followed ReBUILD. Examples include the RENEW study with the anti-lingo monoclonal antibody opicinumab and the CCMR One study with the non-selective retinoid X receptor agonist bexarotene.
Whether there is benefit or failure, “we need to be able to tell what is going on,” Dr. Green said. The reason is that a negative result is not necessarily due to the absence of a meaningful remyelination. Rather, other variables, such as an insufficient number of axons to remyelinate, might explain a lack of effect.
Citing evidence that remyelination and demyelination are often concurrent events, Dr. Green said that there is an urgent need for tools to objectively quantify myelination in order to document that drugs purported to favorably influence myelin repair are doing so. Surrogate markers are potentially unreliable.
“There is an unfortunate tendency in our field to overinterpret atrophy and neurodegeneration and to use those terms too loosely,” Dr. Green said. He said these terms are not interchangeable.
One basis for excitement is the growing support for the theory that oligodendrocyte progenitor cell (OPC) recruitment is critical to the remyelination process. By activating these cells or blocking inhibitors of their activity, experimental evidence suggests new myelin formation can occur. However, a clinically meaningful benefit might still be dependent on multiple additional factors, including the timing of OPC recruitment, Dr. Green explained.
“We might need to provide drugs with a remyelinating effect very early in the process,” he said.
The progress in understanding the interacting factors that define the biology of remyelination is the basis for new enthusiasm about this field, agreed Véronique Miron, PhD, Chair of the Multiple Sclerosis Research, Barlo MS Center, Toronto. Dr. Miron, professor in the Department of Immunology at the University of Toronto, identified the session on remyelination in which Dr. Green spoke as one of the highlights of this year’s ACTRIMS conference.
Late-breaker: Two Remyelinating Drugs with Promise
Consistent with this progress, a late-breaker presentation on two drugs that promote oligodendrocyte formation and remyelination in the experimental setting reinforced the growing array of potential therapeutic targets to generate remyelination. The two drugs, CVL-1001 and CVL-2001, act by inhibiting the cholesterol biosynthesis enzymes sterol 14-demethylase (CYP51) and an emopamil binding protein (EBP).
Multiple studies have suggested that CYP51 and EBP are “key therapeutic targets to promote oligodendrocyte formation,” thereby promoting remyelination, reported Brad T. Lang, PhD, vice president of research for Convelo Therapeutics, Cleveland.
The drugs performed as predicted in animal models, where remyelination was documented, and in promoting human oligodendrocyte formation in human brain organoids. The development of these agents has been accompanied by strategy to measure their activity.
“We established a mechanistic biomarker to assess target engagement in the CNS and periphery to guide the next steps in preclinical and clinical development,” Dr. Lang said.
He called these drugs “first-in-class potential therapies in the field of remyelination.” While he acknowledged that no clinical studies have yet been performed, his late-breaker presentation indicated that many of the criteria identified by Dr. Green, including an ability to penetrate the CNS and a plausible, measurable mechanism of action have been fulfilled.
Dr. Green reported financial relationships with Biogen, Mylan, and Novartis. Dr. Miron reported no potential conflicts of interest.
WEST PALM BEACH, FLORIDA — , according to a summary of the science as well as a late-breaker study presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
In an outline of barriers to remyelinating drugs, including the challenge of delivering well-tolerated therapies into the central nervous system (CNS), Ari J. Green, MD, Chief of the Division of Neuroimmunology and Glial Biology, University of California, San Francisco, spoke specifically about recent progress in drug development.
“The important thing is that once we understand the biology, we can turn barriers into opportunities,” he said as he outlined advances over the 6 years since he led the ReBUILD trial.
“We are thinking of remyelination therapies as something off in the horizon,” said Dr. Green, but “the horizon might be closer than we might imagine.”
The double-blind ReBUILD trial provided the first evidence of activity from a remyelinating drug. In this study, 50 patients with chronic demyelinating optic neuropathy and relapsing-remitting MS were randomized to twice daily doses (5-36 mg) of clemastine fumarate for 90 days followed by placebo for 60 days or to placebo for 60 days followed by active drug for 90 days.
Remyelinating Effect Documented at Multiple Sites
The improvement on the primary endpoint of visual evoked potentials was interpreted as evidence that the therapy had a positive remyelinating effect, and Dr. Green said that the result has been reproduced by more than a dozen other centers.
The theoretical benefit is from a favorable effect on myelin-producing stem cells, but Dr. Green emphasized that theoretical benefits are not enough for moving the field forward. Negative trials with a theoretical potential to generate remyelination both preceded and followed ReBUILD. Examples include the RENEW study with the anti-lingo monoclonal antibody opicinumab and the CCMR One study with the non-selective retinoid X receptor agonist bexarotene.
Whether there is benefit or failure, “we need to be able to tell what is going on,” Dr. Green said. The reason is that a negative result is not necessarily due to the absence of a meaningful remyelination. Rather, other variables, such as an insufficient number of axons to remyelinate, might explain a lack of effect.
Citing evidence that remyelination and demyelination are often concurrent events, Dr. Green said that there is an urgent need for tools to objectively quantify myelination in order to document that drugs purported to favorably influence myelin repair are doing so. Surrogate markers are potentially unreliable.
“There is an unfortunate tendency in our field to overinterpret atrophy and neurodegeneration and to use those terms too loosely,” Dr. Green said. He said these terms are not interchangeable.
One basis for excitement is the growing support for the theory that oligodendrocyte progenitor cell (OPC) recruitment is critical to the remyelination process. By activating these cells or blocking inhibitors of their activity, experimental evidence suggests new myelin formation can occur. However, a clinically meaningful benefit might still be dependent on multiple additional factors, including the timing of OPC recruitment, Dr. Green explained.
“We might need to provide drugs with a remyelinating effect very early in the process,” he said.
The progress in understanding the interacting factors that define the biology of remyelination is the basis for new enthusiasm about this field, agreed Véronique Miron, PhD, Chair of the Multiple Sclerosis Research, Barlo MS Center, Toronto. Dr. Miron, professor in the Department of Immunology at the University of Toronto, identified the session on remyelination in which Dr. Green spoke as one of the highlights of this year’s ACTRIMS conference.
Late-breaker: Two Remyelinating Drugs with Promise
Consistent with this progress, a late-breaker presentation on two drugs that promote oligodendrocyte formation and remyelination in the experimental setting reinforced the growing array of potential therapeutic targets to generate remyelination. The two drugs, CVL-1001 and CVL-2001, act by inhibiting the cholesterol biosynthesis enzymes sterol 14-demethylase (CYP51) and an emopamil binding protein (EBP).
Multiple studies have suggested that CYP51 and EBP are “key therapeutic targets to promote oligodendrocyte formation,” thereby promoting remyelination, reported Brad T. Lang, PhD, vice president of research for Convelo Therapeutics, Cleveland.
The drugs performed as predicted in animal models, where remyelination was documented, and in promoting human oligodendrocyte formation in human brain organoids. The development of these agents has been accompanied by strategy to measure their activity.
“We established a mechanistic biomarker to assess target engagement in the CNS and periphery to guide the next steps in preclinical and clinical development,” Dr. Lang said.
He called these drugs “first-in-class potential therapies in the field of remyelination.” While he acknowledged that no clinical studies have yet been performed, his late-breaker presentation indicated that many of the criteria identified by Dr. Green, including an ability to penetrate the CNS and a plausible, measurable mechanism of action have been fulfilled.
Dr. Green reported financial relationships with Biogen, Mylan, and Novartis. Dr. Miron reported no potential conflicts of interest.
FROM ACTRIMS FORUM 2024
Is Migraine a Forerunner of Multiple Sclerosis?
WEST PALM BEACH, FLORIDA — new research suggested. Investigators found that patients with MS were more likely than controls to develop migraine shortly before disease diagnosis, suggesting the headache type is not a forerunner of MS.
“The risk [of migraine] was concentrated in the year of their first [MS] symptom, or the year prior, instead of many years before,” said lead investigator Vinicius A. Schoeps, MD, MPH, postdoctoral fellow at the University of California San Francisco.
The findings were presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
Is MS a Migraine Trigger?
Worldwide up to 43% of patients with MS report migraine. Recent data point to a 3- to 5-year clinically symptomatic prodromal phase of MS and suggest migraine may be one of its potential constituents. However, the relationship between the two disorders remains unclear.
The investigators wanted to determine whether migraine is part of the MS prodrome because if this is the case, it could provide a potential opportunity for early intervention to delay or prevent the disease.
The team analyzed incidence cases of MS and matched controls in the Kaiser Permanente Southern California health system from 2011 to 2014. Participants took part in structured in-person interviews that included questions about migraine.
The 591 MS cases had an average age of onset at 36 years, with a similar index date for controls. Among the cases, 71% were women, 42% were White, 32% Hispanic, and 21% Black. Almost 40% of cases had obesity. These demographic data were similar in the control group.
In those with MS, 13% had a history of mononucleosis compared with 6% of controls. Epstein-Barr virus, which causes conditions such as mononucleosis, was considered a likely cause of MS.
Migraine was diagnosed before MS onset in 27% of cases and before the index date in 21% of controls (adjusted odds ratio [aOR], 1.36; P = .03). Migraine onset occurred later in cases versus controls (mean, 21 years vs 17 years; P = .008).
Migraine was also more likely to occur at the same time or 1 year prior to MS symptoms or the index date in cases versus controls (4.3% vs 1.3%; aOR, 3.54; P = .002).
“These findings suggest that migraine can be triggered by MS rather than part of the constellation of nonspecific symptoms that constitute the 3- to 5-year-long MS prodrome,” the investigators reported.
“The inflammatory setting of the first MS relapse might be actually triggering the migraine,” Dr. Shoeps said. He added that patients with MS developed migraines later in life.
“There could be a different pathological process in people who have traditional migraine at the most common age where people get their diagnosis of migraine — and have them throughout their lifetime — versus having a migraine at older age and a diagnosis of MS close to that period of time,” he said. However, he noted, the study design does not allow for this type of analysis.
Commenting on the findings, Anibal Chertcoff, MD, PhD, an assistant professor in the Multiple Sclerosis Research Centre at the University of Manitoba, Winnipeg, Manitoba, Canada, noted the study’s large population and well-balanced case and control groups are strengths of the study.
However, Dr. Chertcoff, who was not involved in the research, cautioned that the study is cross-sectional noting that he is “not convinced this is the best type of study design to provide insights into cause-and-effect relationships.”
Dr. Chertcoff added the findings are limited by their reliance on data from a single health system.
Disclosures were not provided. A grant from the National Institute of Neurologic Disorders and Stroke to an author helped support the study. Dr. Chertcoff received funding from MS Canada and the Michael Smith Foundation for Health Research and support from Novartis to attend a scientific meeting.
A version of this article appeared on Medscape.com.
WEST PALM BEACH, FLORIDA — new research suggested. Investigators found that patients with MS were more likely than controls to develop migraine shortly before disease diagnosis, suggesting the headache type is not a forerunner of MS.
“The risk [of migraine] was concentrated in the year of their first [MS] symptom, or the year prior, instead of many years before,” said lead investigator Vinicius A. Schoeps, MD, MPH, postdoctoral fellow at the University of California San Francisco.
The findings were presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
Is MS a Migraine Trigger?
Worldwide up to 43% of patients with MS report migraine. Recent data point to a 3- to 5-year clinically symptomatic prodromal phase of MS and suggest migraine may be one of its potential constituents. However, the relationship between the two disorders remains unclear.
The investigators wanted to determine whether migraine is part of the MS prodrome because if this is the case, it could provide a potential opportunity for early intervention to delay or prevent the disease.
The team analyzed incidence cases of MS and matched controls in the Kaiser Permanente Southern California health system from 2011 to 2014. Participants took part in structured in-person interviews that included questions about migraine.
The 591 MS cases had an average age of onset at 36 years, with a similar index date for controls. Among the cases, 71% were women, 42% were White, 32% Hispanic, and 21% Black. Almost 40% of cases had obesity. These demographic data were similar in the control group.
In those with MS, 13% had a history of mononucleosis compared with 6% of controls. Epstein-Barr virus, which causes conditions such as mononucleosis, was considered a likely cause of MS.
Migraine was diagnosed before MS onset in 27% of cases and before the index date in 21% of controls (adjusted odds ratio [aOR], 1.36; P = .03). Migraine onset occurred later in cases versus controls (mean, 21 years vs 17 years; P = .008).
Migraine was also more likely to occur at the same time or 1 year prior to MS symptoms or the index date in cases versus controls (4.3% vs 1.3%; aOR, 3.54; P = .002).
“These findings suggest that migraine can be triggered by MS rather than part of the constellation of nonspecific symptoms that constitute the 3- to 5-year-long MS prodrome,” the investigators reported.
“The inflammatory setting of the first MS relapse might be actually triggering the migraine,” Dr. Shoeps said. He added that patients with MS developed migraines later in life.
“There could be a different pathological process in people who have traditional migraine at the most common age where people get their diagnosis of migraine — and have them throughout their lifetime — versus having a migraine at older age and a diagnosis of MS close to that period of time,” he said. However, he noted, the study design does not allow for this type of analysis.
Commenting on the findings, Anibal Chertcoff, MD, PhD, an assistant professor in the Multiple Sclerosis Research Centre at the University of Manitoba, Winnipeg, Manitoba, Canada, noted the study’s large population and well-balanced case and control groups are strengths of the study.
However, Dr. Chertcoff, who was not involved in the research, cautioned that the study is cross-sectional noting that he is “not convinced this is the best type of study design to provide insights into cause-and-effect relationships.”
Dr. Chertcoff added the findings are limited by their reliance on data from a single health system.
Disclosures were not provided. A grant from the National Institute of Neurologic Disorders and Stroke to an author helped support the study. Dr. Chertcoff received funding from MS Canada and the Michael Smith Foundation for Health Research and support from Novartis to attend a scientific meeting.
A version of this article appeared on Medscape.com.
WEST PALM BEACH, FLORIDA — new research suggested. Investigators found that patients with MS were more likely than controls to develop migraine shortly before disease diagnosis, suggesting the headache type is not a forerunner of MS.
“The risk [of migraine] was concentrated in the year of their first [MS] symptom, or the year prior, instead of many years before,” said lead investigator Vinicius A. Schoeps, MD, MPH, postdoctoral fellow at the University of California San Francisco.
The findings were presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
Is MS a Migraine Trigger?
Worldwide up to 43% of patients with MS report migraine. Recent data point to a 3- to 5-year clinically symptomatic prodromal phase of MS and suggest migraine may be one of its potential constituents. However, the relationship between the two disorders remains unclear.
The investigators wanted to determine whether migraine is part of the MS prodrome because if this is the case, it could provide a potential opportunity for early intervention to delay or prevent the disease.
The team analyzed incidence cases of MS and matched controls in the Kaiser Permanente Southern California health system from 2011 to 2014. Participants took part in structured in-person interviews that included questions about migraine.
The 591 MS cases had an average age of onset at 36 years, with a similar index date for controls. Among the cases, 71% were women, 42% were White, 32% Hispanic, and 21% Black. Almost 40% of cases had obesity. These demographic data were similar in the control group.
In those with MS, 13% had a history of mononucleosis compared with 6% of controls. Epstein-Barr virus, which causes conditions such as mononucleosis, was considered a likely cause of MS.
Migraine was diagnosed before MS onset in 27% of cases and before the index date in 21% of controls (adjusted odds ratio [aOR], 1.36; P = .03). Migraine onset occurred later in cases versus controls (mean, 21 years vs 17 years; P = .008).
Migraine was also more likely to occur at the same time or 1 year prior to MS symptoms or the index date in cases versus controls (4.3% vs 1.3%; aOR, 3.54; P = .002).
“These findings suggest that migraine can be triggered by MS rather than part of the constellation of nonspecific symptoms that constitute the 3- to 5-year-long MS prodrome,” the investigators reported.
“The inflammatory setting of the first MS relapse might be actually triggering the migraine,” Dr. Shoeps said. He added that patients with MS developed migraines later in life.
“There could be a different pathological process in people who have traditional migraine at the most common age where people get their diagnosis of migraine — and have them throughout their lifetime — versus having a migraine at older age and a diagnosis of MS close to that period of time,” he said. However, he noted, the study design does not allow for this type of analysis.
Commenting on the findings, Anibal Chertcoff, MD, PhD, an assistant professor in the Multiple Sclerosis Research Centre at the University of Manitoba, Winnipeg, Manitoba, Canada, noted the study’s large population and well-balanced case and control groups are strengths of the study.
However, Dr. Chertcoff, who was not involved in the research, cautioned that the study is cross-sectional noting that he is “not convinced this is the best type of study design to provide insights into cause-and-effect relationships.”
Dr. Chertcoff added the findings are limited by their reliance on data from a single health system.
Disclosures were not provided. A grant from the National Institute of Neurologic Disorders and Stroke to an author helped support the study. Dr. Chertcoff received funding from MS Canada and the Michael Smith Foundation for Health Research and support from Novartis to attend a scientific meeting.
A version of this article appeared on Medscape.com.
FROM ACTRIMS FORUM 2024
Seizure Risk Is Nearly Double in Patients With MS
TOPLINE:
, results of a new meta-analysis of randomized controlled trials (RCTs) suggest. Those with a progressive disease phenotype are at particularly high seizure risk.
METHODOLOGY:
- The meta-analysis included 63 phase 3 RCTs with 53,535 patients.
- Most of the studies included in the meta-analysis investigated disease-modifying treatments compared with placebo or an active comparator such as interferon beta, teriflunomide, and dimethyl fumarate, in terms of relapse rate and/or disability progression.
- Researchers extracted relevant information from studies, including MS subtype (clinically isolated syndrome, relapsing-remitting, primary progressive, or secondary progressive MS), mean Expanded Disability Status Scale (EDSS) score, lesion volume on T2-hyperintense sequence, normalized brain volume, and number of seizures or epilepsy events.
- They calculated the pooled effect size of studies on the incidence rate of seizure or epilepsy as the number of events per patient-years and explored which variables influenced the pooled effect size.
TAKEAWAY:
- A total of 120 patients experienced epileptic seizure events over a median follow-up of 2 years, resulting in a pooled incidence rate of 68.0 (95% CI, 49.1-86.9) per 100,000 patient-years, which investigators noted is significantly higher than the general population rate of 34.6.
- Higher seizure incidence rates were found among patients with progressive disease courses, longer time since clinical onset, higher EDSS scores, and lower normalized brain volume; age and T2 lesion volume did not affect the pooled effect size.
- Patients treated with S1PR modulators (fingolimod, ozanimod, ponesimod, and siponimod) had more than double the risk for seizure compared with placebo or comparators (estimated incident seizure risk ratio, 2.45; P = .008).
IN PRACTICE:
“Our findings underscore epilepsy as a significant comorbidity in MS and emphasize the necessity for further research into its triggers, preventive measures and treatment strategies,” the authors wrote.
SOURCE:
The study, led by Valeria Pozzilli, Unit of Neurology, Neurophysiology and Neurobiology, Department of Medicine and Surgery, Campus Bio-Medico University, Roma, Italy, was published online in the Journal of Neurology, Neurosurgery, and Psychiatry.
LIMITATIONS:
As none of the included RCTs considered epilepsy an exclusion criterion, patients with comorbid epilepsy may have been enrolled in these studies. There was significant diversity in reporting of adverse events across studies. While this study’s statistical methodology was robust, the findings can’t be applied directly to individuals due to the risk for ecological fallacy.
DISCLOSURES:
Pozzilli had no relevant conflicts of interests. See paper for disclosures of other authors.
A version of this article appeared on Medscape.com.
TOPLINE:
, results of a new meta-analysis of randomized controlled trials (RCTs) suggest. Those with a progressive disease phenotype are at particularly high seizure risk.
METHODOLOGY:
- The meta-analysis included 63 phase 3 RCTs with 53,535 patients.
- Most of the studies included in the meta-analysis investigated disease-modifying treatments compared with placebo or an active comparator such as interferon beta, teriflunomide, and dimethyl fumarate, in terms of relapse rate and/or disability progression.
- Researchers extracted relevant information from studies, including MS subtype (clinically isolated syndrome, relapsing-remitting, primary progressive, or secondary progressive MS), mean Expanded Disability Status Scale (EDSS) score, lesion volume on T2-hyperintense sequence, normalized brain volume, and number of seizures or epilepsy events.
- They calculated the pooled effect size of studies on the incidence rate of seizure or epilepsy as the number of events per patient-years and explored which variables influenced the pooled effect size.
TAKEAWAY:
- A total of 120 patients experienced epileptic seizure events over a median follow-up of 2 years, resulting in a pooled incidence rate of 68.0 (95% CI, 49.1-86.9) per 100,000 patient-years, which investigators noted is significantly higher than the general population rate of 34.6.
- Higher seizure incidence rates were found among patients with progressive disease courses, longer time since clinical onset, higher EDSS scores, and lower normalized brain volume; age and T2 lesion volume did not affect the pooled effect size.
- Patients treated with S1PR modulators (fingolimod, ozanimod, ponesimod, and siponimod) had more than double the risk for seizure compared with placebo or comparators (estimated incident seizure risk ratio, 2.45; P = .008).
IN PRACTICE:
“Our findings underscore epilepsy as a significant comorbidity in MS and emphasize the necessity for further research into its triggers, preventive measures and treatment strategies,” the authors wrote.
SOURCE:
The study, led by Valeria Pozzilli, Unit of Neurology, Neurophysiology and Neurobiology, Department of Medicine and Surgery, Campus Bio-Medico University, Roma, Italy, was published online in the Journal of Neurology, Neurosurgery, and Psychiatry.
LIMITATIONS:
As none of the included RCTs considered epilepsy an exclusion criterion, patients with comorbid epilepsy may have been enrolled in these studies. There was significant diversity in reporting of adverse events across studies. While this study’s statistical methodology was robust, the findings can’t be applied directly to individuals due to the risk for ecological fallacy.
DISCLOSURES:
Pozzilli had no relevant conflicts of interests. See paper for disclosures of other authors.
A version of this article appeared on Medscape.com.
TOPLINE:
, results of a new meta-analysis of randomized controlled trials (RCTs) suggest. Those with a progressive disease phenotype are at particularly high seizure risk.
METHODOLOGY:
- The meta-analysis included 63 phase 3 RCTs with 53,535 patients.
- Most of the studies included in the meta-analysis investigated disease-modifying treatments compared with placebo or an active comparator such as interferon beta, teriflunomide, and dimethyl fumarate, in terms of relapse rate and/or disability progression.
- Researchers extracted relevant information from studies, including MS subtype (clinically isolated syndrome, relapsing-remitting, primary progressive, or secondary progressive MS), mean Expanded Disability Status Scale (EDSS) score, lesion volume on T2-hyperintense sequence, normalized brain volume, and number of seizures or epilepsy events.
- They calculated the pooled effect size of studies on the incidence rate of seizure or epilepsy as the number of events per patient-years and explored which variables influenced the pooled effect size.
TAKEAWAY:
- A total of 120 patients experienced epileptic seizure events over a median follow-up of 2 years, resulting in a pooled incidence rate of 68.0 (95% CI, 49.1-86.9) per 100,000 patient-years, which investigators noted is significantly higher than the general population rate of 34.6.
- Higher seizure incidence rates were found among patients with progressive disease courses, longer time since clinical onset, higher EDSS scores, and lower normalized brain volume; age and T2 lesion volume did not affect the pooled effect size.
- Patients treated with S1PR modulators (fingolimod, ozanimod, ponesimod, and siponimod) had more than double the risk for seizure compared with placebo or comparators (estimated incident seizure risk ratio, 2.45; P = .008).
IN PRACTICE:
“Our findings underscore epilepsy as a significant comorbidity in MS and emphasize the necessity for further research into its triggers, preventive measures and treatment strategies,” the authors wrote.
SOURCE:
The study, led by Valeria Pozzilli, Unit of Neurology, Neurophysiology and Neurobiology, Department of Medicine and Surgery, Campus Bio-Medico University, Roma, Italy, was published online in the Journal of Neurology, Neurosurgery, and Psychiatry.
LIMITATIONS:
As none of the included RCTs considered epilepsy an exclusion criterion, patients with comorbid epilepsy may have been enrolled in these studies. There was significant diversity in reporting of adverse events across studies. While this study’s statistical methodology was robust, the findings can’t be applied directly to individuals due to the risk for ecological fallacy.
DISCLOSURES:
Pozzilli had no relevant conflicts of interests. See paper for disclosures of other authors.
A version of this article appeared on Medscape.com.
Paramagnetic Rim Lesions Gain Traction as Prognostic Biomarker in MS
WEST PALM BEACH, FLORIDA — , according to one of numerous PRL studies at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
“We think this supports other evidence that PRLs are going to be a useful biomarker for MS,” reported Susan Gauthier, DO, an associate professor of neurology and radiology at Weill Cornell University in New York City.
In a simple study, patients with PRLs at baseline were compared with patients without PRLs over a 4-year period, showing that baseline PRLs correlated with worse cognitive function over time.
Of the study cohort, with a median age of 42 years, 5 patients had clinically isolated syndrome (CIS), 81 had relapsing-remitting MS, and 5 had secondary progressive MS. On baseline MRI, 41% of patients had PRLs.
Cognitive function was tracked over time with the Brief International Cognitive Assessment for MS (BICAMS). The components include the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test (CVLT), and the Brief Visuospatial Memory Test (BVMT).
Univariate linear model relationships were used to look for a relationship between baseline PRLs and cognitive function. Multiple linear models were performed “with all possible iterations” to further explore the most significant variables. At baseline, no differences were seen in any cognitive test between those with or without PRLs.
Cognitive Function Changes at 4 Years
Those with at least one PRL had significantly lower SDMT (P = 0.046) and BVLT (P = 0.0292) at 4 years. There was no significant difference for CVLT scores.
The findings are consistent with the potential for PRLs to serve “as an imaging marker to identify MS patients at risk for cognitive decline,” said Hannah Schwartz, BA, a mentee of Dr. Gauthier and senior clinical research coordinator in the Department of Neurology at Weill Cornell. Ms. Schwartz presented the data at ACTRIMS Forum Cutting Edge symposium.
Over the past 10 years, there has been a growing body of evidence that the presence of PRLs, which are generally described as a spot of demyelination in the central nervous system surrounded by a rim of iron-laden immune cells such as microglia and macrophages, are prognostically important. The sizable number of studies at the ACTRIMS meeting on PRLs, which so far appear to be unique to MS, suggests the field is maturing.
Routine Measurement of PRLs Is Feasible
One set of data from the CAVS-MS study suggest that routine measurement of this biomarker can be integrated into routine imaging. CAVS-MS is a 2-year international multicenter evaluation of MS biomarkers with 11 participating sites that has collected PRL data on 420 patients.
Overall, PRLs were identified in 39% of these patients. However, patients were divided by typical versus atypical presentation, defined by such factors as an uncharacteristic pattern of attacks, accelerated progression, or radiologically isolated lesions. Among the 201 patients with a typical presentation, at least 1 PRL was found in 53%. Among the 219 with atypical presentations, PRLs were seen in only 26%.
The greater rate of PRLs and the greater number of PRLs per positive patient in the typical presentation group (median 3 vs 2) were highly significant (both P < .0001), reported Brian Renner, MD, a research associate in the neuroimaging program, Department of Neurology, Cedars-Sinai Hospital, Los Angeles.
In this analysis, the PRLs were identified by a single experienced rater with T2- and T1-weighted imaging using 2024 North American Imaging in Multiple Sclerosis (NAIMS) criteria for PRL. These criteria were published earlier this year in Brain.
One message from this study is that “PRL measurement in a large multicenter cohort is feasible,” according to Dr. Renner. This is not only important based on the potential role of PRLs as a prognostic biomarker but also for diagnosis, given the fact that PRLs when present appear to confirm a diagnosis of MS.
Misdiagnosis of MS continues to be a problem, and Dr. Renner said that these appear “to be capable of differentiating MS lesions from non-MS disease mimics.” However, he stated that further validation studies are needed.
Can PRLs Be Prevented or Reversed?
The data on PRLs have generated interest in whether they can be prevented or reversed once they appear. This might be dependent on first determining who is at risk. Another study presented at ACTRIMS suggested that it might not be complex. Lesion size might be critical.
In this study, 233 images were evaluated in 64 patients participating in an observational study at the UMass Memorial Medical Center, Worcester, Massachusetts.
In a univariable analysis, a long list of patient factors, disease characteristics, and imaging characteristics correlated with an increased risk of develop PRLs. These included patient age, disease duration, lesion volume, enhancement pattern (ring vs nodular), and use of disease modifying therapies.
When a regression analysis of these factors was performed, “none of the predictive factors on the univariable analyses were significant after including lesion size in the model,” reported Mustafa Al Gburi, MD, a fellow in neuroimaging at UMass.
While his data did show that exposure to steroids did not appear to reduce risk of developing PRLs, he is now running follow-up to see if specific disease-modifying therapies are more or less preventive for the development of PRL. Because of the limited number of patients and follow-up, it is now too early to tell.
Overall, the risk of PRLs appears to grow substantially at a lesion size of greater than 11 mm, Dr. Al Gburi reported. He believes that this might be “a simple bedside marker to determine patients at future risk of chronic active lesions.”
PRLs might not just be a diagnostic and prognostic tool. Dr. Gauthier said that PRLs are at least a theoretical treatment target. While their immediate promise is in monitoring disease, she thinks the evidence would predict a benefit if PRLs could be prevented or reversed.
Dr. Gauthier reports financial relationships with Genentech, Sanofi-Genzyme, and Mallinckrodt. Dr. Renner and Dr. Al Gburi report no potential conflicts of interest.
WEST PALM BEACH, FLORIDA — , according to one of numerous PRL studies at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
“We think this supports other evidence that PRLs are going to be a useful biomarker for MS,” reported Susan Gauthier, DO, an associate professor of neurology and radiology at Weill Cornell University in New York City.
In a simple study, patients with PRLs at baseline were compared with patients without PRLs over a 4-year period, showing that baseline PRLs correlated with worse cognitive function over time.
Of the study cohort, with a median age of 42 years, 5 patients had clinically isolated syndrome (CIS), 81 had relapsing-remitting MS, and 5 had secondary progressive MS. On baseline MRI, 41% of patients had PRLs.
Cognitive function was tracked over time with the Brief International Cognitive Assessment for MS (BICAMS). The components include the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test (CVLT), and the Brief Visuospatial Memory Test (BVMT).
Univariate linear model relationships were used to look for a relationship between baseline PRLs and cognitive function. Multiple linear models were performed “with all possible iterations” to further explore the most significant variables. At baseline, no differences were seen in any cognitive test between those with or without PRLs.
Cognitive Function Changes at 4 Years
Those with at least one PRL had significantly lower SDMT (P = 0.046) and BVLT (P = 0.0292) at 4 years. There was no significant difference for CVLT scores.
The findings are consistent with the potential for PRLs to serve “as an imaging marker to identify MS patients at risk for cognitive decline,” said Hannah Schwartz, BA, a mentee of Dr. Gauthier and senior clinical research coordinator in the Department of Neurology at Weill Cornell. Ms. Schwartz presented the data at ACTRIMS Forum Cutting Edge symposium.
Over the past 10 years, there has been a growing body of evidence that the presence of PRLs, which are generally described as a spot of demyelination in the central nervous system surrounded by a rim of iron-laden immune cells such as microglia and macrophages, are prognostically important. The sizable number of studies at the ACTRIMS meeting on PRLs, which so far appear to be unique to MS, suggests the field is maturing.
Routine Measurement of PRLs Is Feasible
One set of data from the CAVS-MS study suggest that routine measurement of this biomarker can be integrated into routine imaging. CAVS-MS is a 2-year international multicenter evaluation of MS biomarkers with 11 participating sites that has collected PRL data on 420 patients.
Overall, PRLs were identified in 39% of these patients. However, patients were divided by typical versus atypical presentation, defined by such factors as an uncharacteristic pattern of attacks, accelerated progression, or radiologically isolated lesions. Among the 201 patients with a typical presentation, at least 1 PRL was found in 53%. Among the 219 with atypical presentations, PRLs were seen in only 26%.
The greater rate of PRLs and the greater number of PRLs per positive patient in the typical presentation group (median 3 vs 2) were highly significant (both P < .0001), reported Brian Renner, MD, a research associate in the neuroimaging program, Department of Neurology, Cedars-Sinai Hospital, Los Angeles.
In this analysis, the PRLs were identified by a single experienced rater with T2- and T1-weighted imaging using 2024 North American Imaging in Multiple Sclerosis (NAIMS) criteria for PRL. These criteria were published earlier this year in Brain.
One message from this study is that “PRL measurement in a large multicenter cohort is feasible,” according to Dr. Renner. This is not only important based on the potential role of PRLs as a prognostic biomarker but also for diagnosis, given the fact that PRLs when present appear to confirm a diagnosis of MS.
Misdiagnosis of MS continues to be a problem, and Dr. Renner said that these appear “to be capable of differentiating MS lesions from non-MS disease mimics.” However, he stated that further validation studies are needed.
Can PRLs Be Prevented or Reversed?
The data on PRLs have generated interest in whether they can be prevented or reversed once they appear. This might be dependent on first determining who is at risk. Another study presented at ACTRIMS suggested that it might not be complex. Lesion size might be critical.
In this study, 233 images were evaluated in 64 patients participating in an observational study at the UMass Memorial Medical Center, Worcester, Massachusetts.
In a univariable analysis, a long list of patient factors, disease characteristics, and imaging characteristics correlated with an increased risk of develop PRLs. These included patient age, disease duration, lesion volume, enhancement pattern (ring vs nodular), and use of disease modifying therapies.
When a regression analysis of these factors was performed, “none of the predictive factors on the univariable analyses were significant after including lesion size in the model,” reported Mustafa Al Gburi, MD, a fellow in neuroimaging at UMass.
While his data did show that exposure to steroids did not appear to reduce risk of developing PRLs, he is now running follow-up to see if specific disease-modifying therapies are more or less preventive for the development of PRL. Because of the limited number of patients and follow-up, it is now too early to tell.
Overall, the risk of PRLs appears to grow substantially at a lesion size of greater than 11 mm, Dr. Al Gburi reported. He believes that this might be “a simple bedside marker to determine patients at future risk of chronic active lesions.”
PRLs might not just be a diagnostic and prognostic tool. Dr. Gauthier said that PRLs are at least a theoretical treatment target. While their immediate promise is in monitoring disease, she thinks the evidence would predict a benefit if PRLs could be prevented or reversed.
Dr. Gauthier reports financial relationships with Genentech, Sanofi-Genzyme, and Mallinckrodt. Dr. Renner and Dr. Al Gburi report no potential conflicts of interest.
WEST PALM BEACH, FLORIDA — , according to one of numerous PRL studies at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
“We think this supports other evidence that PRLs are going to be a useful biomarker for MS,” reported Susan Gauthier, DO, an associate professor of neurology and radiology at Weill Cornell University in New York City.
In a simple study, patients with PRLs at baseline were compared with patients without PRLs over a 4-year period, showing that baseline PRLs correlated with worse cognitive function over time.
Of the study cohort, with a median age of 42 years, 5 patients had clinically isolated syndrome (CIS), 81 had relapsing-remitting MS, and 5 had secondary progressive MS. On baseline MRI, 41% of patients had PRLs.
Cognitive function was tracked over time with the Brief International Cognitive Assessment for MS (BICAMS). The components include the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test (CVLT), and the Brief Visuospatial Memory Test (BVMT).
Univariate linear model relationships were used to look for a relationship between baseline PRLs and cognitive function. Multiple linear models were performed “with all possible iterations” to further explore the most significant variables. At baseline, no differences were seen in any cognitive test between those with or without PRLs.
Cognitive Function Changes at 4 Years
Those with at least one PRL had significantly lower SDMT (P = 0.046) and BVLT (P = 0.0292) at 4 years. There was no significant difference for CVLT scores.
The findings are consistent with the potential for PRLs to serve “as an imaging marker to identify MS patients at risk for cognitive decline,” said Hannah Schwartz, BA, a mentee of Dr. Gauthier and senior clinical research coordinator in the Department of Neurology at Weill Cornell. Ms. Schwartz presented the data at ACTRIMS Forum Cutting Edge symposium.
Over the past 10 years, there has been a growing body of evidence that the presence of PRLs, which are generally described as a spot of demyelination in the central nervous system surrounded by a rim of iron-laden immune cells such as microglia and macrophages, are prognostically important. The sizable number of studies at the ACTRIMS meeting on PRLs, which so far appear to be unique to MS, suggests the field is maturing.
Routine Measurement of PRLs Is Feasible
One set of data from the CAVS-MS study suggest that routine measurement of this biomarker can be integrated into routine imaging. CAVS-MS is a 2-year international multicenter evaluation of MS biomarkers with 11 participating sites that has collected PRL data on 420 patients.
Overall, PRLs were identified in 39% of these patients. However, patients were divided by typical versus atypical presentation, defined by such factors as an uncharacteristic pattern of attacks, accelerated progression, or radiologically isolated lesions. Among the 201 patients with a typical presentation, at least 1 PRL was found in 53%. Among the 219 with atypical presentations, PRLs were seen in only 26%.
The greater rate of PRLs and the greater number of PRLs per positive patient in the typical presentation group (median 3 vs 2) were highly significant (both P < .0001), reported Brian Renner, MD, a research associate in the neuroimaging program, Department of Neurology, Cedars-Sinai Hospital, Los Angeles.
In this analysis, the PRLs were identified by a single experienced rater with T2- and T1-weighted imaging using 2024 North American Imaging in Multiple Sclerosis (NAIMS) criteria for PRL. These criteria were published earlier this year in Brain.
One message from this study is that “PRL measurement in a large multicenter cohort is feasible,” according to Dr. Renner. This is not only important based on the potential role of PRLs as a prognostic biomarker but also for diagnosis, given the fact that PRLs when present appear to confirm a diagnosis of MS.
Misdiagnosis of MS continues to be a problem, and Dr. Renner said that these appear “to be capable of differentiating MS lesions from non-MS disease mimics.” However, he stated that further validation studies are needed.
Can PRLs Be Prevented or Reversed?
The data on PRLs have generated interest in whether they can be prevented or reversed once they appear. This might be dependent on first determining who is at risk. Another study presented at ACTRIMS suggested that it might not be complex. Lesion size might be critical.
In this study, 233 images were evaluated in 64 patients participating in an observational study at the UMass Memorial Medical Center, Worcester, Massachusetts.
In a univariable analysis, a long list of patient factors, disease characteristics, and imaging characteristics correlated with an increased risk of develop PRLs. These included patient age, disease duration, lesion volume, enhancement pattern (ring vs nodular), and use of disease modifying therapies.
When a regression analysis of these factors was performed, “none of the predictive factors on the univariable analyses were significant after including lesion size in the model,” reported Mustafa Al Gburi, MD, a fellow in neuroimaging at UMass.
While his data did show that exposure to steroids did not appear to reduce risk of developing PRLs, he is now running follow-up to see if specific disease-modifying therapies are more or less preventive for the development of PRL. Because of the limited number of patients and follow-up, it is now too early to tell.
Overall, the risk of PRLs appears to grow substantially at a lesion size of greater than 11 mm, Dr. Al Gburi reported. He believes that this might be “a simple bedside marker to determine patients at future risk of chronic active lesions.”
PRLs might not just be a diagnostic and prognostic tool. Dr. Gauthier said that PRLs are at least a theoretical treatment target. While their immediate promise is in monitoring disease, she thinks the evidence would predict a benefit if PRLs could be prevented or reversed.
Dr. Gauthier reports financial relationships with Genentech, Sanofi-Genzyme, and Mallinckrodt. Dr. Renner and Dr. Al Gburi report no potential conflicts of interest.
FROM ACRIMS FORUM 2024
Improved Communication Center Stage in Multiple Sclerosis
This transcript has been edited for clarity.
Joseph R. Berger, MD: Hi. I'm Dr Joseph Berger, and I'm joined for this Care Cues conversation with my patient, Michelle Biloon, who has had multiple sclerosis (MS) for the past 6 years. Hello, Michelle. Welcome.
Michelle Biloon: Thank you, Dr Berger.
Berger: Can you tell us a little bit about yourself, how you came to understand you had MS, and how you've done since the diagnosis was rendered?
Biloon: Yeah. It was a very short diagnosis period for me. In the winter of 2017, I started experiencing dizzy spells, and I didn't really know why. I eventually went to my primary care clinic where my doctor is, and they did blood work. Then, they did a CT and didn't see anything, and I just kind of kept feeling worse.
Then, finally, I went to an ENT just to see if it was maybe related to my ears. The ENT actually said, "You need to go to the ER and get an MRI." And while I was in the MRI, I could feel the dizzy spells. And I thought, Well, something is happening. I don't know what it is. And then a resident came in and said that they saw lesions on my brain, and they knew that it was going to be MS or something like it.
Berger: How did you feel about that?
Biloon: At the time, I was kind of glad to hear it was something. And I just asked her if, like, you die from it. That was the first thing I asked. It was like falling off a cliff.
It was making it hard for me to function in what I was doing, which was stand-up comedy, because of the cognitive issues I was having, the cognitive fog. That was how I ended up with you. Right away, you talked to me and were actually able to introduce to me some new medications that are out and are phenomenally better for MS plus were not pills or shots every day. It's made my MS over the years a lot more manageable.
Berger: I'd like to pick up on a couple of things you said.
Biloon: Sure.
Berger: One is, because most people envision MS as this terrible, crippling illness that's going to leave them wheelchair-bound, deprived of their profession, finding it difficult to stay in a marriage it's vested with what has been termed "lamentable results." And one of the first things that we as physicians have to do is to calm people down and say, "You know what. You have MS. You're going to be just fine. Trust me. We have wonderful medications for what you have, and we'll take care of it." In fact, I've made a habit of telling people quit worrying. You hired me to worry for you.
Biloon: Yep.
Berger: And I think that's helpful.
Biloon: I've been just so appreciative of that. There's a balance of being condescended to — do you know what I mean — and also being given information. I'm very sensitive to that balance because I consider myself an intelligent person. And you're being put in a position where someone knows more than you, and you have to listen.
Berger: One of the other challenges we face is getting somebody on a treatment. And we elected to put you on an intravenous therapy every 6 months.
Biloon: Especially because as a stand-up comedian, I was traveling a lot, doing these every-6-months infusion, especially with the high efficacy rate that it had been reported from what we had read and the low amount of side effects. I mean, just those things together was just something that seemed the easiest for me.
Berger: So did you encounter any challenges when we first got you started on the infusion therapy?
Biloon: The first infusion I got was at the hospital. But then after that, I had to go to the suburbs, to a center out there for the infusion. That was difficult because to get a ride out there and a ride back — it was a long trip for someone to wait with me. Taking an Uber is expensive, so was it for me to drive. You don't feel good for a couple of days after. So that was how it was, and I complained about it. Probably at every appointment we had, I complained about it.
Berger: Yeah. So some of the challenges you talked about are very, very common. As a physician on medications myself, I can tell you that I am not particularly compliant. And what I love about infusion therapies is that I know that the patient is getting their medicine. Because when they don't show up for a scheduled appointment, I'm called, and I know.
Biloon: I do have a bit of an allergic reaction to the drug. But that's been easily managed over time. Now, the drug infusions are actually being done at my home, which makes the whole process twice-a-year–world's better.
Berger: But there are other barriers that people confront other than the initiation of drugs. Had you encountered any?
Biloon: I think the problem that I had more so was finding the drugs that would manage some of my symptoms. It took a couple of years to sort of figure out what that would be, both with figuring them out and both dealing with insurance on certain medications.
Berger: That's one sort of problem that we confront. The other, of course, are those individuals who, for a variety of reasons, have difficulty with the diagnosis because of their backgrounds. And they may be sociocultural in nature. Every time you go to the physical therapist, it's some degree of money.
Now for some people, it's trivial. But for others, it's a considerable amount of money, relative to what it is that they earn. And you simply have to work within those confines as best you can.
We do have various programs that help people. So we try to employ them. There are, in addition to the sociocultural barriers, language barriers that we often confront. We, in our situation here in a large city, have a very large migrant population.
Fortunately, most of the people speak languages that either you speak as well, or there's somebody in the next room that speaks pretty well. But that's not always the case. So we do have an interpreter service that has to be employed.
Biloon: I cannot imagine the nuance in speaking to people from different ages and different backgrounds, who have different types of lifestyles, for them to understand.
Berger: I don't write at a computer. I think that really degrades the patient-physician relationship. What I do is I obtain a history. I do it on a piece of paper with a pen or a pencil.
I recapitulate them to the patient in paraphrasing it, to make sure that I have gotten it right and that they understand what I think I heard. That, I think, has been enormously helpful in helping people understand what may happen in the absence of treatment and why the treatment is important. That you can do, regardless of what the person's background is. So that's how I approach it.
Biloon: How do you deal with patients when they're not on the same page with you?
Berger: One important thing is that you have to be patient. That is something that it took me 50 years in medicine to learn. And then accepting the patient's opinion and saying, "All right, go home and think about it," because you often don't convince them when they're in the office with you.
Biloon: I did have a little bit of a cushion between my diagnosis and when we actually saw each other, where I was able to really sit in my thoughts on the different treatments and stuff. By the time that we were able to talk, it reassured me on that was the right plan.
Berger: I'm curious what your experience has been with our MS center.
Biloon: Through the portal, every time I need something, I'm usually reaching out, keeping you up-to-date on my primary care or whether it's trying to get a refill on one of my medications that I have to reach out. I really do feel that having that team there, being able to reach out, that's been extremely helpful to have and keeps me very secure because that's all I really need, especially during the pandemic, right? Because then I was very isolated and dealing with going through MS. So it was great to at least — and I did — shoot off emails or texts in the portal, and that's usually primarily how I communicated.
Berger: I will tell you, in my opinion, maybe nine out of 10 messages in the portal or calls that we get simply require reassurance.
Biloon: Yes.
Berger: You just either pick up the phone or shoot back a note, say, "This is not your MS. Don't worry about it." I mean, the most important thing for me is to keep people from worrying because that doesn't solve any problem.
Biloon: No, and it causes stress, which causes fatigue. I mean, it's a bad cycle.
Berger: In the past year, you've actually felt better, and you've gone back to performing. It sounds like the volume of performances has gotten back to what it was pre-illness. What do you see for the future?
Biloon: What I see is traveling more for stand-up and doing the sort of clubs and cities that I had kind of stopped doing from before I was diagnosed, so 2017 and prior to that. And then also even working on other things, writing and maybe even doing sort of books or one-person shows that even talk about sort of my struggles with MS and kind of coming back to where I am. I'm looking forward to the future, and I hope that that's the track I can keep going on.
Berger: I see no reason why you shouldn't.
Biloon: Thank you.
Berger: Michelle, thank you very much for joining me today in this conversation.
Biloon: Thank you so much for having me. It's been really wonderful to be able to sit down here with you.
Joseph R. Berger, MD, has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Celgene/Bristol-Myers Squibb; Cellevolve; EMD Serono/Merck/Genentech; Genzyme; Janssen/Johnson & Johnson; Morphic; Novartis; Roche; Sanofi; Takeda; TG Therapeutics; MAPI; Excision Bio
Received research grant from: Genentech/Roche
Michelle Biloon has disclosed no relevant financial relationships
This transcript has been edited for clarity.
Joseph R. Berger, MD: Hi. I'm Dr Joseph Berger, and I'm joined for this Care Cues conversation with my patient, Michelle Biloon, who has had multiple sclerosis (MS) for the past 6 years. Hello, Michelle. Welcome.
Michelle Biloon: Thank you, Dr Berger.
Berger: Can you tell us a little bit about yourself, how you came to understand you had MS, and how you've done since the diagnosis was rendered?
Biloon: Yeah. It was a very short diagnosis period for me. In the winter of 2017, I started experiencing dizzy spells, and I didn't really know why. I eventually went to my primary care clinic where my doctor is, and they did blood work. Then, they did a CT and didn't see anything, and I just kind of kept feeling worse.
Then, finally, I went to an ENT just to see if it was maybe related to my ears. The ENT actually said, "You need to go to the ER and get an MRI." And while I was in the MRI, I could feel the dizzy spells. And I thought, Well, something is happening. I don't know what it is. And then a resident came in and said that they saw lesions on my brain, and they knew that it was going to be MS or something like it.
Berger: How did you feel about that?
Biloon: At the time, I was kind of glad to hear it was something. And I just asked her if, like, you die from it. That was the first thing I asked. It was like falling off a cliff.
It was making it hard for me to function in what I was doing, which was stand-up comedy, because of the cognitive issues I was having, the cognitive fog. That was how I ended up with you. Right away, you talked to me and were actually able to introduce to me some new medications that are out and are phenomenally better for MS plus were not pills or shots every day. It's made my MS over the years a lot more manageable.
Berger: I'd like to pick up on a couple of things you said.
Biloon: Sure.
Berger: One is, because most people envision MS as this terrible, crippling illness that's going to leave them wheelchair-bound, deprived of their profession, finding it difficult to stay in a marriage it's vested with what has been termed "lamentable results." And one of the first things that we as physicians have to do is to calm people down and say, "You know what. You have MS. You're going to be just fine. Trust me. We have wonderful medications for what you have, and we'll take care of it." In fact, I've made a habit of telling people quit worrying. You hired me to worry for you.
Biloon: Yep.
Berger: And I think that's helpful.
Biloon: I've been just so appreciative of that. There's a balance of being condescended to — do you know what I mean — and also being given information. I'm very sensitive to that balance because I consider myself an intelligent person. And you're being put in a position where someone knows more than you, and you have to listen.
Berger: One of the other challenges we face is getting somebody on a treatment. And we elected to put you on an intravenous therapy every 6 months.
Biloon: Especially because as a stand-up comedian, I was traveling a lot, doing these every-6-months infusion, especially with the high efficacy rate that it had been reported from what we had read and the low amount of side effects. I mean, just those things together was just something that seemed the easiest for me.
Berger: So did you encounter any challenges when we first got you started on the infusion therapy?
Biloon: The first infusion I got was at the hospital. But then after that, I had to go to the suburbs, to a center out there for the infusion. That was difficult because to get a ride out there and a ride back — it was a long trip for someone to wait with me. Taking an Uber is expensive, so was it for me to drive. You don't feel good for a couple of days after. So that was how it was, and I complained about it. Probably at every appointment we had, I complained about it.
Berger: Yeah. So some of the challenges you talked about are very, very common. As a physician on medications myself, I can tell you that I am not particularly compliant. And what I love about infusion therapies is that I know that the patient is getting their medicine. Because when they don't show up for a scheduled appointment, I'm called, and I know.
Biloon: I do have a bit of an allergic reaction to the drug. But that's been easily managed over time. Now, the drug infusions are actually being done at my home, which makes the whole process twice-a-year–world's better.
Berger: But there are other barriers that people confront other than the initiation of drugs. Had you encountered any?
Biloon: I think the problem that I had more so was finding the drugs that would manage some of my symptoms. It took a couple of years to sort of figure out what that would be, both with figuring them out and both dealing with insurance on certain medications.
Berger: That's one sort of problem that we confront. The other, of course, are those individuals who, for a variety of reasons, have difficulty with the diagnosis because of their backgrounds. And they may be sociocultural in nature. Every time you go to the physical therapist, it's some degree of money.
Now for some people, it's trivial. But for others, it's a considerable amount of money, relative to what it is that they earn. And you simply have to work within those confines as best you can.
We do have various programs that help people. So we try to employ them. There are, in addition to the sociocultural barriers, language barriers that we often confront. We, in our situation here in a large city, have a very large migrant population.
Fortunately, most of the people speak languages that either you speak as well, or there's somebody in the next room that speaks pretty well. But that's not always the case. So we do have an interpreter service that has to be employed.
Biloon: I cannot imagine the nuance in speaking to people from different ages and different backgrounds, who have different types of lifestyles, for them to understand.
Berger: I don't write at a computer. I think that really degrades the patient-physician relationship. What I do is I obtain a history. I do it on a piece of paper with a pen or a pencil.
I recapitulate them to the patient in paraphrasing it, to make sure that I have gotten it right and that they understand what I think I heard. That, I think, has been enormously helpful in helping people understand what may happen in the absence of treatment and why the treatment is important. That you can do, regardless of what the person's background is. So that's how I approach it.
Biloon: How do you deal with patients when they're not on the same page with you?
Berger: One important thing is that you have to be patient. That is something that it took me 50 years in medicine to learn. And then accepting the patient's opinion and saying, "All right, go home and think about it," because you often don't convince them when they're in the office with you.
Biloon: I did have a little bit of a cushion between my diagnosis and when we actually saw each other, where I was able to really sit in my thoughts on the different treatments and stuff. By the time that we were able to talk, it reassured me on that was the right plan.
Berger: I'm curious what your experience has been with our MS center.
Biloon: Through the portal, every time I need something, I'm usually reaching out, keeping you up-to-date on my primary care or whether it's trying to get a refill on one of my medications that I have to reach out. I really do feel that having that team there, being able to reach out, that's been extremely helpful to have and keeps me very secure because that's all I really need, especially during the pandemic, right? Because then I was very isolated and dealing with going through MS. So it was great to at least — and I did — shoot off emails or texts in the portal, and that's usually primarily how I communicated.
Berger: I will tell you, in my opinion, maybe nine out of 10 messages in the portal or calls that we get simply require reassurance.
Biloon: Yes.
Berger: You just either pick up the phone or shoot back a note, say, "This is not your MS. Don't worry about it." I mean, the most important thing for me is to keep people from worrying because that doesn't solve any problem.
Biloon: No, and it causes stress, which causes fatigue. I mean, it's a bad cycle.
Berger: In the past year, you've actually felt better, and you've gone back to performing. It sounds like the volume of performances has gotten back to what it was pre-illness. What do you see for the future?
Biloon: What I see is traveling more for stand-up and doing the sort of clubs and cities that I had kind of stopped doing from before I was diagnosed, so 2017 and prior to that. And then also even working on other things, writing and maybe even doing sort of books or one-person shows that even talk about sort of my struggles with MS and kind of coming back to where I am. I'm looking forward to the future, and I hope that that's the track I can keep going on.
Berger: I see no reason why you shouldn't.
Biloon: Thank you.
Berger: Michelle, thank you very much for joining me today in this conversation.
Biloon: Thank you so much for having me. It's been really wonderful to be able to sit down here with you.
Joseph R. Berger, MD, has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Celgene/Bristol-Myers Squibb; Cellevolve; EMD Serono/Merck/Genentech; Genzyme; Janssen/Johnson & Johnson; Morphic; Novartis; Roche; Sanofi; Takeda; TG Therapeutics; MAPI; Excision Bio
Received research grant from: Genentech/Roche
Michelle Biloon has disclosed no relevant financial relationships
This transcript has been edited for clarity.
Joseph R. Berger, MD: Hi. I'm Dr Joseph Berger, and I'm joined for this Care Cues conversation with my patient, Michelle Biloon, who has had multiple sclerosis (MS) for the past 6 years. Hello, Michelle. Welcome.
Michelle Biloon: Thank you, Dr Berger.
Berger: Can you tell us a little bit about yourself, how you came to understand you had MS, and how you've done since the diagnosis was rendered?
Biloon: Yeah. It was a very short diagnosis period for me. In the winter of 2017, I started experiencing dizzy spells, and I didn't really know why. I eventually went to my primary care clinic where my doctor is, and they did blood work. Then, they did a CT and didn't see anything, and I just kind of kept feeling worse.
Then, finally, I went to an ENT just to see if it was maybe related to my ears. The ENT actually said, "You need to go to the ER and get an MRI." And while I was in the MRI, I could feel the dizzy spells. And I thought, Well, something is happening. I don't know what it is. And then a resident came in and said that they saw lesions on my brain, and they knew that it was going to be MS or something like it.
Berger: How did you feel about that?
Biloon: At the time, I was kind of glad to hear it was something. And I just asked her if, like, you die from it. That was the first thing I asked. It was like falling off a cliff.
It was making it hard for me to function in what I was doing, which was stand-up comedy, because of the cognitive issues I was having, the cognitive fog. That was how I ended up with you. Right away, you talked to me and were actually able to introduce to me some new medications that are out and are phenomenally better for MS plus were not pills or shots every day. It's made my MS over the years a lot more manageable.
Berger: I'd like to pick up on a couple of things you said.
Biloon: Sure.
Berger: One is, because most people envision MS as this terrible, crippling illness that's going to leave them wheelchair-bound, deprived of their profession, finding it difficult to stay in a marriage it's vested with what has been termed "lamentable results." And one of the first things that we as physicians have to do is to calm people down and say, "You know what. You have MS. You're going to be just fine. Trust me. We have wonderful medications for what you have, and we'll take care of it." In fact, I've made a habit of telling people quit worrying. You hired me to worry for you.
Biloon: Yep.
Berger: And I think that's helpful.
Biloon: I've been just so appreciative of that. There's a balance of being condescended to — do you know what I mean — and also being given information. I'm very sensitive to that balance because I consider myself an intelligent person. And you're being put in a position where someone knows more than you, and you have to listen.
Berger: One of the other challenges we face is getting somebody on a treatment. And we elected to put you on an intravenous therapy every 6 months.
Biloon: Especially because as a stand-up comedian, I was traveling a lot, doing these every-6-months infusion, especially with the high efficacy rate that it had been reported from what we had read and the low amount of side effects. I mean, just those things together was just something that seemed the easiest for me.
Berger: So did you encounter any challenges when we first got you started on the infusion therapy?
Biloon: The first infusion I got was at the hospital. But then after that, I had to go to the suburbs, to a center out there for the infusion. That was difficult because to get a ride out there and a ride back — it was a long trip for someone to wait with me. Taking an Uber is expensive, so was it for me to drive. You don't feel good for a couple of days after. So that was how it was, and I complained about it. Probably at every appointment we had, I complained about it.
Berger: Yeah. So some of the challenges you talked about are very, very common. As a physician on medications myself, I can tell you that I am not particularly compliant. And what I love about infusion therapies is that I know that the patient is getting their medicine. Because when they don't show up for a scheduled appointment, I'm called, and I know.
Biloon: I do have a bit of an allergic reaction to the drug. But that's been easily managed over time. Now, the drug infusions are actually being done at my home, which makes the whole process twice-a-year–world's better.
Berger: But there are other barriers that people confront other than the initiation of drugs. Had you encountered any?
Biloon: I think the problem that I had more so was finding the drugs that would manage some of my symptoms. It took a couple of years to sort of figure out what that would be, both with figuring them out and both dealing with insurance on certain medications.
Berger: That's one sort of problem that we confront. The other, of course, are those individuals who, for a variety of reasons, have difficulty with the diagnosis because of their backgrounds. And they may be sociocultural in nature. Every time you go to the physical therapist, it's some degree of money.
Now for some people, it's trivial. But for others, it's a considerable amount of money, relative to what it is that they earn. And you simply have to work within those confines as best you can.
We do have various programs that help people. So we try to employ them. There are, in addition to the sociocultural barriers, language barriers that we often confront. We, in our situation here in a large city, have a very large migrant population.
Fortunately, most of the people speak languages that either you speak as well, or there's somebody in the next room that speaks pretty well. But that's not always the case. So we do have an interpreter service that has to be employed.
Biloon: I cannot imagine the nuance in speaking to people from different ages and different backgrounds, who have different types of lifestyles, for them to understand.
Berger: I don't write at a computer. I think that really degrades the patient-physician relationship. What I do is I obtain a history. I do it on a piece of paper with a pen or a pencil.
I recapitulate them to the patient in paraphrasing it, to make sure that I have gotten it right and that they understand what I think I heard. That, I think, has been enormously helpful in helping people understand what may happen in the absence of treatment and why the treatment is important. That you can do, regardless of what the person's background is. So that's how I approach it.
Biloon: How do you deal with patients when they're not on the same page with you?
Berger: One important thing is that you have to be patient. That is something that it took me 50 years in medicine to learn. And then accepting the patient's opinion and saying, "All right, go home and think about it," because you often don't convince them when they're in the office with you.
Biloon: I did have a little bit of a cushion between my diagnosis and when we actually saw each other, where I was able to really sit in my thoughts on the different treatments and stuff. By the time that we were able to talk, it reassured me on that was the right plan.
Berger: I'm curious what your experience has been with our MS center.
Biloon: Through the portal, every time I need something, I'm usually reaching out, keeping you up-to-date on my primary care or whether it's trying to get a refill on one of my medications that I have to reach out. I really do feel that having that team there, being able to reach out, that's been extremely helpful to have and keeps me very secure because that's all I really need, especially during the pandemic, right? Because then I was very isolated and dealing with going through MS. So it was great to at least — and I did — shoot off emails or texts in the portal, and that's usually primarily how I communicated.
Berger: I will tell you, in my opinion, maybe nine out of 10 messages in the portal or calls that we get simply require reassurance.
Biloon: Yes.
Berger: You just either pick up the phone or shoot back a note, say, "This is not your MS. Don't worry about it." I mean, the most important thing for me is to keep people from worrying because that doesn't solve any problem.
Biloon: No, and it causes stress, which causes fatigue. I mean, it's a bad cycle.
Berger: In the past year, you've actually felt better, and you've gone back to performing. It sounds like the volume of performances has gotten back to what it was pre-illness. What do you see for the future?
Biloon: What I see is traveling more for stand-up and doing the sort of clubs and cities that I had kind of stopped doing from before I was diagnosed, so 2017 and prior to that. And then also even working on other things, writing and maybe even doing sort of books or one-person shows that even talk about sort of my struggles with MS and kind of coming back to where I am. I'm looking forward to the future, and I hope that that's the track I can keep going on.
Berger: I see no reason why you shouldn't.
Biloon: Thank you.
Berger: Michelle, thank you very much for joining me today in this conversation.
Biloon: Thank you so much for having me. It's been really wonderful to be able to sit down here with you.
Joseph R. Berger, MD, has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Celgene/Bristol-Myers Squibb; Cellevolve; EMD Serono/Merck/Genentech; Genzyme; Janssen/Johnson & Johnson; Morphic; Novartis; Roche; Sanofi; Takeda; TG Therapeutics; MAPI; Excision Bio
Received research grant from: Genentech/Roche
Michelle Biloon has disclosed no relevant financial relationships
Autoimmune Disease Risk May Rise Following Cushing Disease Remission After Surgery
Patients with Cushing disease have an increased risk for new-onset autoimmune disease in the 3 years after surgical remission, according to a new retrospective study published on February 20 in Annals of Internal Medicine.
Outcomes for patients with Cushing disease were compared against those with nonfunctioning pituitary adenomas (NFPAs). New-onset autoimmune disease occurred in 10.4% with Cushing disease and 1.6% among patients with NFPA (hazard ratio, 7.80; 95% CI, 2.88-21.10).
“Understanding and recognizing new and recurrent autoimmune disease in this setting is important to avoid misclassifying such patients with glucocorticoid withdrawal syndrome, which could result in failure to treat underlying autoimmune disease, as well as erroneous diagnosis of steroid withdrawal cases,” wrote Dennis Delasi Nyanyo of Massachusetts General Hospital and Harvard Medical School, Boston, and colleagues.
Given the general population’s annual incidence of major autoimmune diseases, estimated at about 100 cases per 100,000 people, and the 3-year incidence of 10.4% found in this study’s cohort, “our findings suggest that Cushing disease remission may trigger development of autoimmune disease,” the authors wrote.
Monitor Patients With Family History of Autoimmune Disease?
The study results were not necessarily surprising to Anthony P. Heaney, MD, PhD, an endocrinologist and professor of medicine at the University of California, Los Angeles, because past research has raised similar questions. The authors’ suggestion that the rapid postsurgical drop in cortisol that occurs as a result of treating Cushing disease becomes some sort of autoimmune trigger is interesting but remains speculative, Dr. Heaney pointed out.
If future evidence supports that possibility, “it would suggest, in terms of managing those patients in the postoperative setting, that there may be some merit to giving them higher concentrations of glucocorticoids for a short period of time,” Dr. Heaney said, thereby bringing their levels down more gradually rather than taking them off a cliff, in a sense. Or, if more evidence bears out the authors’ hypothesis, another approach might be treating patients with medicine to bring down the cortisol before surgery, though there are challenges to that approach, Dr. Heaney said.
At the same time, those who developed new autoimmune disease remain a small subset of patients with Cushing disease, so such approaches may become only potentially appropriate to consider in patients with risk factors, such as a family history of autoimmune disease.
The researchers conducted a retrospective chart review of adult patients who underwent transsphenoidal surgery for either Cushing disease or NFPA at Massachusetts General Hospital between 2005 and 2019.
The study involved 194 patients with Cushing disease who had postsurgical remission and at least one follow-up visit with a pituitary expert and 92 patients with NFPA who were matched to patients with Cushing disease based on age and sex. The authors regarded autoimmune disease diagnosed within 36 months of the surgery to be temporally associated with Cushing disease remission. Among the autoimmune diseases considered were “rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus, autoimmune thyroiditis, celiac disease, psoriasis, vitiligo, autoimmune neuropathy, multiple sclerosis, myasthenia gravis, and ulcerative colitis.”
Patients differed in average body mass index and tumor size, but family history of autoimmune disease was similar in both groups. Average BMI was 34.5 in the Cushing group and 29.5 in the NFPA group. Average tumor size was 5.7 mm in the Cushing group and 21.3 mm in the NFPA group.
Before surgery, 2.9% of patients with Cushing disease and 15.4% of patients with NFPA had central hypothyroidism, and 8% in the Cushing group and 56.8% in the NFPA group had hyperprolactinemia. Central adrenal insufficiency occurred in 11% with NFPA and in all with Cushing disease, by definition.
After surgery, 93.8% in the Cushing group and 16.5% in the NFPA group had adrenal insufficiency. In addition, patients with Cushing disease had lower postsurgical nadir serum cortisol levels (63.8 nmol/L) than those with NFPA (282.3 nmol/L).
Of the 17 patients with Cushing disease — all women — who developed autoimmune disease within 3 years, 6 had a personal history of autoimmune disease and 7 had a family history of it. In addition, 41.2% of them had adrenal insufficiency when they developed the new autoimmune disease. Among the diseases were six autoimmune thyroiditis cases, three Sjögren syndrome cases, and two autoimmune seronegative spondyloarthropathy.
Dr. Heaney said he found it interesting that more than half of the new autoimmune diseases in patients with Cushing disease were related to the thyroid. “In this kind of setting, where you have a patient who has been producing too much steroid over a period of time and then you take that away, it’s almost like you release a brake on the TSH [thyroid-stimulating hormone],” Dr. Heaney said. “So, there’s probably some rebound in TSH that occurs, and that could be driving the thyroiditis, to some extent, that we see in these patients.”
Only one patient with NFPA developed new-onset autoimmune disease, a woman who developed Graves disease 22 months after surgery. When the researchers excluded patients in both groups with central hypothyroidism, new-onset autoimmune disease was still significantly higher (11.4%) in the Cushing group than in the NFPA group (1.9%; HR, 7.02; 95% CI, 2.54-19.39).
Could Postoperative Adrenal Insufficiency Contribute to Risk?
Within the Cushing cohort, those who developed autoimmune disease had a lower BMI (31.8 vs 34.8) and larger tumor size (7.2 vs 5.6 mm) than those who didn’t develop new autoimmune disease. Patients who developed autoimmune disease also had a lower baseline urine free cortisol ratio (2.7 vs 6.3) before surgery and more family history of autoimmune disease (41.2% vs 20.9%) than those who didn’t develop one.
“The higher prevalence of adrenal insufficiency and the lower nadir serum cortisol levels in the Cushing disease group suggest that the postoperative adrenal insufficiency in the Cushing disease group might have contributed to autoimmune disease pathogenesis,” the authors wrote. “This finding is clinically significant because cortisol plays a pivotal role in modulating the immune system.”
Most postoperative management among patients with Cushing disease was similar, with all but one patient receiving 0.5 or 1 mg daily dexamethasone within the first week after surgery. (The one outlier received 5 mg daily prednisone.) However, fewer patients who developed autoimmune disease (17.6%) received supraphysiologic doses of glucocorticoid — equivalent to at least 25 mg hydrocortisone — compared with patients who didn’t develop autoimmune disease (41.8%).
“Although the daily average hydrocortisone equivalent replacement doses within the first month and during long-term follow-up were within the physiologic range in both subgroups, patients with Cushing disease who had autoimmune disease received slightly lower doses of glucocorticoid replacement within the first month after surgery,” the authors reported. “The immediate postoperative period might be a critical window where supraphysiologic glucocorticoids seem to be protective with regard to development of autoimmune disease,” they wrote, though they acknowledged the study’s retrospective design as a limitation in drawing that conclusion.
At the least, they suggested that new symptoms in patients with Cushing disease, particularly those with a family history of autoimmune disease, should prompt investigation of potential autoimmune disease.
Recordati Rare Diseases funded the study. The research was also conducted with support from Harvard Catalyst (the Harvard Clinical and Translational Science Center) as well as financial contributions from Harvard University and its affiliated academic healthcare centers. One author reported holding stocks in Pfizer and Amgen, and another reported receiving consulting fees from Corcept. Dr. Heaney reported receiving institutional grants for trials from Corcept, Ascendis, Crinetics, and Sparrow Pharm; serving on the advisory board for Xeris, Recordati, Corcept, Novo Nordisk, Lundbeck, and Crinetics; and serving as a speaker for Chiesi, Novo Nordisk, and Corcept.
A version of this article appeared on Medscape.com.
Patients with Cushing disease have an increased risk for new-onset autoimmune disease in the 3 years after surgical remission, according to a new retrospective study published on February 20 in Annals of Internal Medicine.
Outcomes for patients with Cushing disease were compared against those with nonfunctioning pituitary adenomas (NFPAs). New-onset autoimmune disease occurred in 10.4% with Cushing disease and 1.6% among patients with NFPA (hazard ratio, 7.80; 95% CI, 2.88-21.10).
“Understanding and recognizing new and recurrent autoimmune disease in this setting is important to avoid misclassifying such patients with glucocorticoid withdrawal syndrome, which could result in failure to treat underlying autoimmune disease, as well as erroneous diagnosis of steroid withdrawal cases,” wrote Dennis Delasi Nyanyo of Massachusetts General Hospital and Harvard Medical School, Boston, and colleagues.
Given the general population’s annual incidence of major autoimmune diseases, estimated at about 100 cases per 100,000 people, and the 3-year incidence of 10.4% found in this study’s cohort, “our findings suggest that Cushing disease remission may trigger development of autoimmune disease,” the authors wrote.
Monitor Patients With Family History of Autoimmune Disease?
The study results were not necessarily surprising to Anthony P. Heaney, MD, PhD, an endocrinologist and professor of medicine at the University of California, Los Angeles, because past research has raised similar questions. The authors’ suggestion that the rapid postsurgical drop in cortisol that occurs as a result of treating Cushing disease becomes some sort of autoimmune trigger is interesting but remains speculative, Dr. Heaney pointed out.
If future evidence supports that possibility, “it would suggest, in terms of managing those patients in the postoperative setting, that there may be some merit to giving them higher concentrations of glucocorticoids for a short period of time,” Dr. Heaney said, thereby bringing their levels down more gradually rather than taking them off a cliff, in a sense. Or, if more evidence bears out the authors’ hypothesis, another approach might be treating patients with medicine to bring down the cortisol before surgery, though there are challenges to that approach, Dr. Heaney said.
At the same time, those who developed new autoimmune disease remain a small subset of patients with Cushing disease, so such approaches may become only potentially appropriate to consider in patients with risk factors, such as a family history of autoimmune disease.
The researchers conducted a retrospective chart review of adult patients who underwent transsphenoidal surgery for either Cushing disease or NFPA at Massachusetts General Hospital between 2005 and 2019.
The study involved 194 patients with Cushing disease who had postsurgical remission and at least one follow-up visit with a pituitary expert and 92 patients with NFPA who were matched to patients with Cushing disease based on age and sex. The authors regarded autoimmune disease diagnosed within 36 months of the surgery to be temporally associated with Cushing disease remission. Among the autoimmune diseases considered were “rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus, autoimmune thyroiditis, celiac disease, psoriasis, vitiligo, autoimmune neuropathy, multiple sclerosis, myasthenia gravis, and ulcerative colitis.”
Patients differed in average body mass index and tumor size, but family history of autoimmune disease was similar in both groups. Average BMI was 34.5 in the Cushing group and 29.5 in the NFPA group. Average tumor size was 5.7 mm in the Cushing group and 21.3 mm in the NFPA group.
Before surgery, 2.9% of patients with Cushing disease and 15.4% of patients with NFPA had central hypothyroidism, and 8% in the Cushing group and 56.8% in the NFPA group had hyperprolactinemia. Central adrenal insufficiency occurred in 11% with NFPA and in all with Cushing disease, by definition.
After surgery, 93.8% in the Cushing group and 16.5% in the NFPA group had adrenal insufficiency. In addition, patients with Cushing disease had lower postsurgical nadir serum cortisol levels (63.8 nmol/L) than those with NFPA (282.3 nmol/L).
Of the 17 patients with Cushing disease — all women — who developed autoimmune disease within 3 years, 6 had a personal history of autoimmune disease and 7 had a family history of it. In addition, 41.2% of them had adrenal insufficiency when they developed the new autoimmune disease. Among the diseases were six autoimmune thyroiditis cases, three Sjögren syndrome cases, and two autoimmune seronegative spondyloarthropathy.
Dr. Heaney said he found it interesting that more than half of the new autoimmune diseases in patients with Cushing disease were related to the thyroid. “In this kind of setting, where you have a patient who has been producing too much steroid over a period of time and then you take that away, it’s almost like you release a brake on the TSH [thyroid-stimulating hormone],” Dr. Heaney said. “So, there’s probably some rebound in TSH that occurs, and that could be driving the thyroiditis, to some extent, that we see in these patients.”
Only one patient with NFPA developed new-onset autoimmune disease, a woman who developed Graves disease 22 months after surgery. When the researchers excluded patients in both groups with central hypothyroidism, new-onset autoimmune disease was still significantly higher (11.4%) in the Cushing group than in the NFPA group (1.9%; HR, 7.02; 95% CI, 2.54-19.39).
Could Postoperative Adrenal Insufficiency Contribute to Risk?
Within the Cushing cohort, those who developed autoimmune disease had a lower BMI (31.8 vs 34.8) and larger tumor size (7.2 vs 5.6 mm) than those who didn’t develop new autoimmune disease. Patients who developed autoimmune disease also had a lower baseline urine free cortisol ratio (2.7 vs 6.3) before surgery and more family history of autoimmune disease (41.2% vs 20.9%) than those who didn’t develop one.
“The higher prevalence of adrenal insufficiency and the lower nadir serum cortisol levels in the Cushing disease group suggest that the postoperative adrenal insufficiency in the Cushing disease group might have contributed to autoimmune disease pathogenesis,” the authors wrote. “This finding is clinically significant because cortisol plays a pivotal role in modulating the immune system.”
Most postoperative management among patients with Cushing disease was similar, with all but one patient receiving 0.5 or 1 mg daily dexamethasone within the first week after surgery. (The one outlier received 5 mg daily prednisone.) However, fewer patients who developed autoimmune disease (17.6%) received supraphysiologic doses of glucocorticoid — equivalent to at least 25 mg hydrocortisone — compared with patients who didn’t develop autoimmune disease (41.8%).
“Although the daily average hydrocortisone equivalent replacement doses within the first month and during long-term follow-up were within the physiologic range in both subgroups, patients with Cushing disease who had autoimmune disease received slightly lower doses of glucocorticoid replacement within the first month after surgery,” the authors reported. “The immediate postoperative period might be a critical window where supraphysiologic glucocorticoids seem to be protective with regard to development of autoimmune disease,” they wrote, though they acknowledged the study’s retrospective design as a limitation in drawing that conclusion.
At the least, they suggested that new symptoms in patients with Cushing disease, particularly those with a family history of autoimmune disease, should prompt investigation of potential autoimmune disease.
Recordati Rare Diseases funded the study. The research was also conducted with support from Harvard Catalyst (the Harvard Clinical and Translational Science Center) as well as financial contributions from Harvard University and its affiliated academic healthcare centers. One author reported holding stocks in Pfizer and Amgen, and another reported receiving consulting fees from Corcept. Dr. Heaney reported receiving institutional grants for trials from Corcept, Ascendis, Crinetics, and Sparrow Pharm; serving on the advisory board for Xeris, Recordati, Corcept, Novo Nordisk, Lundbeck, and Crinetics; and serving as a speaker for Chiesi, Novo Nordisk, and Corcept.
A version of this article appeared on Medscape.com.
Patients with Cushing disease have an increased risk for new-onset autoimmune disease in the 3 years after surgical remission, according to a new retrospective study published on February 20 in Annals of Internal Medicine.
Outcomes for patients with Cushing disease were compared against those with nonfunctioning pituitary adenomas (NFPAs). New-onset autoimmune disease occurred in 10.4% with Cushing disease and 1.6% among patients with NFPA (hazard ratio, 7.80; 95% CI, 2.88-21.10).
“Understanding and recognizing new and recurrent autoimmune disease in this setting is important to avoid misclassifying such patients with glucocorticoid withdrawal syndrome, which could result in failure to treat underlying autoimmune disease, as well as erroneous diagnosis of steroid withdrawal cases,” wrote Dennis Delasi Nyanyo of Massachusetts General Hospital and Harvard Medical School, Boston, and colleagues.
Given the general population’s annual incidence of major autoimmune diseases, estimated at about 100 cases per 100,000 people, and the 3-year incidence of 10.4% found in this study’s cohort, “our findings suggest that Cushing disease remission may trigger development of autoimmune disease,” the authors wrote.
Monitor Patients With Family History of Autoimmune Disease?
The study results were not necessarily surprising to Anthony P. Heaney, MD, PhD, an endocrinologist and professor of medicine at the University of California, Los Angeles, because past research has raised similar questions. The authors’ suggestion that the rapid postsurgical drop in cortisol that occurs as a result of treating Cushing disease becomes some sort of autoimmune trigger is interesting but remains speculative, Dr. Heaney pointed out.
If future evidence supports that possibility, “it would suggest, in terms of managing those patients in the postoperative setting, that there may be some merit to giving them higher concentrations of glucocorticoids for a short period of time,” Dr. Heaney said, thereby bringing their levels down more gradually rather than taking them off a cliff, in a sense. Or, if more evidence bears out the authors’ hypothesis, another approach might be treating patients with medicine to bring down the cortisol before surgery, though there are challenges to that approach, Dr. Heaney said.
At the same time, those who developed new autoimmune disease remain a small subset of patients with Cushing disease, so such approaches may become only potentially appropriate to consider in patients with risk factors, such as a family history of autoimmune disease.
The researchers conducted a retrospective chart review of adult patients who underwent transsphenoidal surgery for either Cushing disease or NFPA at Massachusetts General Hospital between 2005 and 2019.
The study involved 194 patients with Cushing disease who had postsurgical remission and at least one follow-up visit with a pituitary expert and 92 patients with NFPA who were matched to patients with Cushing disease based on age and sex. The authors regarded autoimmune disease diagnosed within 36 months of the surgery to be temporally associated with Cushing disease remission. Among the autoimmune diseases considered were “rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus, autoimmune thyroiditis, celiac disease, psoriasis, vitiligo, autoimmune neuropathy, multiple sclerosis, myasthenia gravis, and ulcerative colitis.”
Patients differed in average body mass index and tumor size, but family history of autoimmune disease was similar in both groups. Average BMI was 34.5 in the Cushing group and 29.5 in the NFPA group. Average tumor size was 5.7 mm in the Cushing group and 21.3 mm in the NFPA group.
Before surgery, 2.9% of patients with Cushing disease and 15.4% of patients with NFPA had central hypothyroidism, and 8% in the Cushing group and 56.8% in the NFPA group had hyperprolactinemia. Central adrenal insufficiency occurred in 11% with NFPA and in all with Cushing disease, by definition.
After surgery, 93.8% in the Cushing group and 16.5% in the NFPA group had adrenal insufficiency. In addition, patients with Cushing disease had lower postsurgical nadir serum cortisol levels (63.8 nmol/L) than those with NFPA (282.3 nmol/L).
Of the 17 patients with Cushing disease — all women — who developed autoimmune disease within 3 years, 6 had a personal history of autoimmune disease and 7 had a family history of it. In addition, 41.2% of them had adrenal insufficiency when they developed the new autoimmune disease. Among the diseases were six autoimmune thyroiditis cases, three Sjögren syndrome cases, and two autoimmune seronegative spondyloarthropathy.
Dr. Heaney said he found it interesting that more than half of the new autoimmune diseases in patients with Cushing disease were related to the thyroid. “In this kind of setting, where you have a patient who has been producing too much steroid over a period of time and then you take that away, it’s almost like you release a brake on the TSH [thyroid-stimulating hormone],” Dr. Heaney said. “So, there’s probably some rebound in TSH that occurs, and that could be driving the thyroiditis, to some extent, that we see in these patients.”
Only one patient with NFPA developed new-onset autoimmune disease, a woman who developed Graves disease 22 months after surgery. When the researchers excluded patients in both groups with central hypothyroidism, new-onset autoimmune disease was still significantly higher (11.4%) in the Cushing group than in the NFPA group (1.9%; HR, 7.02; 95% CI, 2.54-19.39).
Could Postoperative Adrenal Insufficiency Contribute to Risk?
Within the Cushing cohort, those who developed autoimmune disease had a lower BMI (31.8 vs 34.8) and larger tumor size (7.2 vs 5.6 mm) than those who didn’t develop new autoimmune disease. Patients who developed autoimmune disease also had a lower baseline urine free cortisol ratio (2.7 vs 6.3) before surgery and more family history of autoimmune disease (41.2% vs 20.9%) than those who didn’t develop one.
“The higher prevalence of adrenal insufficiency and the lower nadir serum cortisol levels in the Cushing disease group suggest that the postoperative adrenal insufficiency in the Cushing disease group might have contributed to autoimmune disease pathogenesis,” the authors wrote. “This finding is clinically significant because cortisol plays a pivotal role in modulating the immune system.”
Most postoperative management among patients with Cushing disease was similar, with all but one patient receiving 0.5 or 1 mg daily dexamethasone within the first week after surgery. (The one outlier received 5 mg daily prednisone.) However, fewer patients who developed autoimmune disease (17.6%) received supraphysiologic doses of glucocorticoid — equivalent to at least 25 mg hydrocortisone — compared with patients who didn’t develop autoimmune disease (41.8%).
“Although the daily average hydrocortisone equivalent replacement doses within the first month and during long-term follow-up were within the physiologic range in both subgroups, patients with Cushing disease who had autoimmune disease received slightly lower doses of glucocorticoid replacement within the first month after surgery,” the authors reported. “The immediate postoperative period might be a critical window where supraphysiologic glucocorticoids seem to be protective with regard to development of autoimmune disease,” they wrote, though they acknowledged the study’s retrospective design as a limitation in drawing that conclusion.
At the least, they suggested that new symptoms in patients with Cushing disease, particularly those with a family history of autoimmune disease, should prompt investigation of potential autoimmune disease.
Recordati Rare Diseases funded the study. The research was also conducted with support from Harvard Catalyst (the Harvard Clinical and Translational Science Center) as well as financial contributions from Harvard University and its affiliated academic healthcare centers. One author reported holding stocks in Pfizer and Amgen, and another reported receiving consulting fees from Corcept. Dr. Heaney reported receiving institutional grants for trials from Corcept, Ascendis, Crinetics, and Sparrow Pharm; serving on the advisory board for Xeris, Recordati, Corcept, Novo Nordisk, Lundbeck, and Crinetics; and serving as a speaker for Chiesi, Novo Nordisk, and Corcept.
A version of this article appeared on Medscape.com.
FROM ANNALS OF INTERNAL MEDICINE