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The first therapy targeted at modifying a mutant gene associated with amyotrophic lateral sclerosis (ALS), approved in early 2023, has offered reassurance that the biology of ALS, when known, is targetable. Historically, the disease has been considered a clinical diagnosis, but the progress in identifying molecular mechanisms is permitting ALS to be understood as a biological entity and suggests rationally targeted therapies will be the way forward following the inadequacy of nonselective drugs.

Despite a narrow indication, the only therapy targeted at an ALS-associated gene so far, SOD1 ALS, supports the premise that the biology of ALS can be modified, according to Christina N. Fournier, MD, an associate professor in the Department of Neurology, Emory University, Atlanta, Georgia.

About 15% of ALS Has An Identifiable Genetic Cause

A family history of ALS is present in about 10% of cases. A genetic cause can be identified in approximately 15%. Cases without an identifiable genetic etiology are considered sporadic. So far, the only approved therapy that modifies the function of a gene associated with ALS is tofersen (Qalsody, Biogen), an antisense oligonucleotide. Tofersen inhibits RNA transcription of the superoxide dismutase 1 (SOD1) gene to decrease production of the SOD1 protein.

This first gene therapy for ALS is a breakthrough, but it is indicated for only a small proportion of ALS patients. Even though SOD1 gene mutations represent the second most common genetic cause of ALS after the C90rf72 gene, the proportion of patients who are candidates for tofersen is low. Efficacy is expected only in about 1% of those with familial ALS and 1% of those with sporadic ALS, or about 2% of all patients with ALS.

The evidence of benefit from a treatment with a specific target has provided the basis for concluding that “we are onto something,” Dr. Fournier said. An expert in ALS, she sees reason for excitement about the prospects in treatment with the growing focus on the underlying pathways of disease rather than the downstream consequences.

“The hope is that new gene-targeted therapies will be developed in the future to treat the broader ALS population,” said Dr. Fournier, explaining that the move toward rationally targeted treatments, whether related to gene mutations or independent molecular pathways of ALS progression, has created excitement in the field.

Numerous Disease Processes Are Potentially Targetable

As treatments are developed to address nongenetic molecular processes that contribute to the risk or progression of ALS, such as neuroinflammation or abnormal protein misfolding and aggregation, individualized treatment is likely to become key. Just as not all genetic cases share mutations in the same gene, the key molecular drivers of disease are likely to differ between patients. If so, it is hoped that biomarkers reflective of this underlying biology can be identified to appropriately target treatments.

“The excitement behind the newer targets in clinical trials is based on both basic science and early clinical data that support treatment based on specific drivers of disease,” Dr. Fournier said.

In 2023 and just prior to the FDA approval of tofersen, a set of expert consensus guidelines were published calling for genetic testing to be offered to all patients with ALS. These recommendations suggested that SOD1, C9orf72, FUS, and TARDBP should be included routinely into the panel of genes evaluated, calling for additional genes to be added as they emerge as potential therapeutic targets.

Even before these guidelines were released, genetic testing was already being offered at many centers with expertise in ALS. The rationale was to differentiate ALS with a genetic etiology from that with a nongenetic etiology, as well as to counsel family members when genetic risk was identified, but genetic testing has now assumed new urgency. In addition to the potential for offering a specific treatment for SOD1-related ALS, patients with other genetic forms of disease might be candidates for genetically focused clinical trials.

Genetic testing should be performed as soon as a diagnosis of ALS is made, according to Dr. Fournier. Although not all patients have accepted genetic testing, particularly in the past when there was no immediate clinical gain from establishing the presence of a genetic mutation, she said there is no longer any controversy about clinical relevance.
 

Genetic Testing Is Key to Genetic Therapies

“We do not want to miss the opportunity to treat patients when we have the chance,” said Dr. Fournier, referring to both the likely advantage of an early start of the approved gene therapy as well as the opportunity to participate in a clinical trial with other gene therapies in development.

Prior to the approval of tofersen, riluzole and edaravone had been the only disease-modifying agents in widespread use, but these drugs are nonspecific. There are no established biomarkers for establishing which patients are most likely to benefit.

In the case of riluzole, a pivotal trial conducted 30 years ago showed a survival benefit relative to placebo at 12 months (74% vs. 58%; P = 0.014). In a retrospective study published in 2022 that evaluated survival in a database of 4778 ALS patients of whom 3446 received riluzole, early diagnosis of ALS and prompt treatment with riluzole was associated with longer survival than delayed treatment. The benefit of edaravone has been validated with clinical measures, such as the revised Amyotrophic Lateral Sclerosis Functional Scale (ALSFRS-R).

The retrospective study of riluzole provides the basis for predicting better benefits from disease-modifying therapies if started earlier in the course of ALS. The same premise will be explored with newer therapies that target ALS-associated genes.

Early Treatment Presumed More Effective

“We think that earlier treatment in the course of ALS is probably better for gene therapies as well,” Dr. Fournier said. She cautioned that follow-up is not yet long enough to confirm a survival benefit with tofersen, but she said it is reasonable to anticipate better and longer response when neurologic damage is limited. Citing the effect of gene therapy in spinal muscular atrophy (SMA), where progression is halted if gene therapy is initiated early in life, Dr. Fourier suggested that the emphasis on early treatment stems from the low likelihood for treatments to reverse functional impairments.

“It is conceivable that future treatments might be developed to reverse symptoms, but current drug development is largely aimed at slowing progression,” she explained. Under some circumstances, halting progression has the potential to allow some function to be regained, but as the etiologies of ALS and the pathways of progression are better understood, she believes that all targeted therapy will be started as early as possible to prevent rather than treat neurological damage.

Tofersen, the gene therapy for SOD1-ALS, has provided an opportunity to test the idea that it may be possible to prevent ALS. In a phase 3 trial called ATLAS, unaffected carriers of SOD1 variants that are associated with aggressive disease and high or complete penetrance are enrolled for a run-in phase (Part A) during which participants are followed for a rise in neurofilament light chain (NfL) levels. Based on a previous natural history study called the Pre-Symptomatic Familial ALS (Pre-fALS) study, NfL rises in the serum of unaffected SOD1 carriers prior to phenoconversion. A low NfL is an entry criterion for ATLAS.

ATLAS End Point Is Reduction in Phenoconversion to Clinically Manifest ALS

People in whom NfL rises above a predefined threshold during the run-in stage will be eligible for randomization (Part B) to receive either tofersen or placebo. Efficacy will be measured by comparing the rates of phenoconversion to clinically manifest ALS between those who receive placebo and those who receive tofersen.

Two other groups enrolled in ATLAS will be followed on open-label tofersen. One comprises people who phenoconvert during Part B and the other comprises those who develop ALS during the run-in and therefore are not enrolled in Part B. These patients, forming Parts C and D of the study, provide another set of data to evaluate whether earlier rather than later introduction of therapy provides better outcomes.

“There is a lot of interest and optimism about the trial,” said Dr. Fournier, who praised the trial design and thinks the hypothesis being explored “makes sense.”

Michael Benatar, MD, PhD, professor of neurology and public health, University of Miami School of Medicine, Miami, Florida, is the principal investigator of ATLAS and also leads the Pre-Symptomatic Familial ALS study together with a colleague, Joanne Wuu, Associate Director of Research at the University of Miami ALS Center. The hope from these initiatives, according to Dr. Fournier, is that ATLAS will offer broader learnings beyond just the SOD1 population, providing critical information about the optimal timing of treatment initiation.

The benefit from targeting genes considered causative for ALS is not yet a sure thing. A clinical trial targeting C9orf72, for example, failed to support an approvable therapy. There is a trial of a gene therapy for the FUS variant that is ongoing. Yet, the introduction of a gene therapy for SOD1 variant ALS has already established that highly targeted therapies can be effective, an important step forward after so many failed treatment trials with nonspecific drugs.

“We are seeing more and more therapies being developed to address specific ALS biology,” said Dr. Fournier, who predicts a pivot toward conceptualizing ALS as an array of pathologies rather than one disorder driven by a single mechanism. More effort is being directed to recognizing phenotypes as well as genotypes. Hopefully, more biomarkers that distinguish between ALS variants will emerge and help in individualizing treatment.

“We are not there yet, but I think many of us in the field see this as a way forward,” she said.
 

Multidisciplinary Care, Symptomatic Management, and Palliative Care Are Still Essential for ALS

Disease-modifying therapies are the ultimate goal in ALS, but Dr. Fournier said that the other side of the equation is multidisciplinary and palliative care. To the extent that almost all ALS therapies only modify the course of disease modestly, palliative care remains the cornerstone of day-to-day care.

“Multidisciplinary and palliative care are not necessarily novel, but they are still critically important. There are clear data to show that multidisciplinary care improves functional status and quality of life, and that this is meaningful to patients,” Dr. Fournier said.

There have been numerous improvements in the areas of multidisciplinary and palliative care, some of which can be credited to advancing technology. In centers of excellence, the multidisciplinary approach has been focused on helping patients sustain a sense of independence and self-worth.

Now robotics, devices, and software are being increasingly employed to extend patient capabilities even in relatively advanced stages of disease, according to Dr. Fournier. As one example, she cited current work in brain-computer interfaces to record electrical activity in the central nervous system to allow patients to communicate even when speech is impaired.

A focus on patient-centered clinical care is appropriate because it is the best current opportunity to improve the lives of patients with ALS. Clinically, this work is very rewarding, according to Dr. Fournier, who described ALS patients overall as generally ”very invested in advocacy and research initiatives and motivated to help others,” Dr. Fournier said.

“The diagnosis can be tough, but there is satisfaction in helping these patients navigate toward an acceptable and meaningful quality of life. They typically give a lot back,” she added.

Overall, there is a sense of progress in ALS, even though it remains a uniformly fatal disease. Dr. Fournier expressed hope that clinical research is reaching a tipping point and an emphasis on targeted treatments after a long list of failed trials over the past 30 years. However, with only one approved therapy modifying an ALS-associated gene, this approach is still in its early stages.

Dr. Fournier has financial relationships with Amylyx, Biogen, Corcept, Denali, Mitsubishi QurAlis, and Tanabe.
 

Suggested Reading

Benatar M et al. Design of a Randomized, Placebo-Controlled, Phase 3 Trial of Tofersen Initiated in Clinically Presymptomatic SOD1 Variant Carriers: the ATLAS Study. Neurotherapeutics. 2022 Jul;19(4):1248-1258. doi: 10.1007/s13311-022-01237-4.

Geronimo A et al. Ten Years of Riluzole Use in a Tertiary ALS Clinic. Muscle Nerve. 2022 Jun;65(6):659-666. doi: 10.1002/mus.27541.

Roggenbuck J et al. Evidence-Based Consensus Guidelines for ALS Genetic Testing and Counseling. Ann Clin Transl Neurol. 2023 Nov;10(11):2074-2091. doi: 10.1002/acn3.51895.

The first therapy targeted at modifying a mutant gene associated with amyotrophic lateral sclerosis (ALS), approved in early 2023, has offered reassurance that the biology of ALS, when known, is targetable. Historically, the disease has been considered a clinical diagnosis, but the progress in identifying molecular mechanisms is permitting ALS to be understood as a biological entity and suggests rationally targeted therapies will be the way forward following the inadequacy of nonselective drugs.

Despite a narrow indication, the only therapy targeted at an ALS-associated gene so far, SOD1 ALS, supports the premise that the biology of ALS can be modified, according to Christina N. Fournier, MD, an associate professor in the Department of Neurology, Emory University, Atlanta, Georgia.

About 15% of ALS Has An Identifiable Genetic Cause

A family history of ALS is present in about 10% of cases. A genetic cause can be identified in approximately 15%. Cases without an identifiable genetic etiology are considered sporadic. So far, the only approved therapy that modifies the function of a gene associated with ALS is tofersen (Qalsody, Biogen), an antisense oligonucleotide. Tofersen inhibits RNA transcription of the superoxide dismutase 1 (SOD1) gene to decrease production of the SOD1 protein.

This first gene therapy for ALS is a breakthrough, but it is indicated for only a small proportion of ALS patients. Even though SOD1 gene mutations represent the second most common genetic cause of ALS after the C90rf72 gene, the proportion of patients who are candidates for tofersen is low. Efficacy is expected only in about 1% of those with familial ALS and 1% of those with sporadic ALS, or about 2% of all patients with ALS.

The evidence of benefit from a treatment with a specific target has provided the basis for concluding that “we are onto something,” Dr. Fournier said. An expert in ALS, she sees reason for excitement about the prospects in treatment with the growing focus on the underlying pathways of disease rather than the downstream consequences.

“The hope is that new gene-targeted therapies will be developed in the future to treat the broader ALS population,” said Dr. Fournier, explaining that the move toward rationally targeted treatments, whether related to gene mutations or independent molecular pathways of ALS progression, has created excitement in the field.

Numerous Disease Processes Are Potentially Targetable

As treatments are developed to address nongenetic molecular processes that contribute to the risk or progression of ALS, such as neuroinflammation or abnormal protein misfolding and aggregation, individualized treatment is likely to become key. Just as not all genetic cases share mutations in the same gene, the key molecular drivers of disease are likely to differ between patients. If so, it is hoped that biomarkers reflective of this underlying biology can be identified to appropriately target treatments.

“The excitement behind the newer targets in clinical trials is based on both basic science and early clinical data that support treatment based on specific drivers of disease,” Dr. Fournier said.

In 2023 and just prior to the FDA approval of tofersen, a set of expert consensus guidelines were published calling for genetic testing to be offered to all patients with ALS. These recommendations suggested that SOD1, C9orf72, FUS, and TARDBP should be included routinely into the panel of genes evaluated, calling for additional genes to be added as they emerge as potential therapeutic targets.

Even before these guidelines were released, genetic testing was already being offered at many centers with expertise in ALS. The rationale was to differentiate ALS with a genetic etiology from that with a nongenetic etiology, as well as to counsel family members when genetic risk was identified, but genetic testing has now assumed new urgency. In addition to the potential for offering a specific treatment for SOD1-related ALS, patients with other genetic forms of disease might be candidates for genetically focused clinical trials.

Genetic testing should be performed as soon as a diagnosis of ALS is made, according to Dr. Fournier. Although not all patients have accepted genetic testing, particularly in the past when there was no immediate clinical gain from establishing the presence of a genetic mutation, she said there is no longer any controversy about clinical relevance.
 

Genetic Testing Is Key to Genetic Therapies

“We do not want to miss the opportunity to treat patients when we have the chance,” said Dr. Fournier, referring to both the likely advantage of an early start of the approved gene therapy as well as the opportunity to participate in a clinical trial with other gene therapies in development.

Prior to the approval of tofersen, riluzole and edaravone had been the only disease-modifying agents in widespread use, but these drugs are nonspecific. There are no established biomarkers for establishing which patients are most likely to benefit.

In the case of riluzole, a pivotal trial conducted 30 years ago showed a survival benefit relative to placebo at 12 months (74% vs. 58%; P = 0.014). In a retrospective study published in 2022 that evaluated survival in a database of 4778 ALS patients of whom 3446 received riluzole, early diagnosis of ALS and prompt treatment with riluzole was associated with longer survival than delayed treatment. The benefit of edaravone has been validated with clinical measures, such as the revised Amyotrophic Lateral Sclerosis Functional Scale (ALSFRS-R).

The retrospective study of riluzole provides the basis for predicting better benefits from disease-modifying therapies if started earlier in the course of ALS. The same premise will be explored with newer therapies that target ALS-associated genes.

Early Treatment Presumed More Effective

“We think that earlier treatment in the course of ALS is probably better for gene therapies as well,” Dr. Fournier said. She cautioned that follow-up is not yet long enough to confirm a survival benefit with tofersen, but she said it is reasonable to anticipate better and longer response when neurologic damage is limited. Citing the effect of gene therapy in spinal muscular atrophy (SMA), where progression is halted if gene therapy is initiated early in life, Dr. Fourier suggested that the emphasis on early treatment stems from the low likelihood for treatments to reverse functional impairments.

“It is conceivable that future treatments might be developed to reverse symptoms, but current drug development is largely aimed at slowing progression,” she explained. Under some circumstances, halting progression has the potential to allow some function to be regained, but as the etiologies of ALS and the pathways of progression are better understood, she believes that all targeted therapy will be started as early as possible to prevent rather than treat neurological damage.

Tofersen, the gene therapy for SOD1-ALS, has provided an opportunity to test the idea that it may be possible to prevent ALS. In a phase 3 trial called ATLAS, unaffected carriers of SOD1 variants that are associated with aggressive disease and high or complete penetrance are enrolled for a run-in phase (Part A) during which participants are followed for a rise in neurofilament light chain (NfL) levels. Based on a previous natural history study called the Pre-Symptomatic Familial ALS (Pre-fALS) study, NfL rises in the serum of unaffected SOD1 carriers prior to phenoconversion. A low NfL is an entry criterion for ATLAS.

ATLAS End Point Is Reduction in Phenoconversion to Clinically Manifest ALS

People in whom NfL rises above a predefined threshold during the run-in stage will be eligible for randomization (Part B) to receive either tofersen or placebo. Efficacy will be measured by comparing the rates of phenoconversion to clinically manifest ALS between those who receive placebo and those who receive tofersen.

Two other groups enrolled in ATLAS will be followed on open-label tofersen. One comprises people who phenoconvert during Part B and the other comprises those who develop ALS during the run-in and therefore are not enrolled in Part B. These patients, forming Parts C and D of the study, provide another set of data to evaluate whether earlier rather than later introduction of therapy provides better outcomes.

“There is a lot of interest and optimism about the trial,” said Dr. Fournier, who praised the trial design and thinks the hypothesis being explored “makes sense.”

Michael Benatar, MD, PhD, professor of neurology and public health, University of Miami School of Medicine, Miami, Florida, is the principal investigator of ATLAS and also leads the Pre-Symptomatic Familial ALS study together with a colleague, Joanne Wuu, Associate Director of Research at the University of Miami ALS Center. The hope from these initiatives, according to Dr. Fournier, is that ATLAS will offer broader learnings beyond just the SOD1 population, providing critical information about the optimal timing of treatment initiation.

The benefit from targeting genes considered causative for ALS is not yet a sure thing. A clinical trial targeting C9orf72, for example, failed to support an approvable therapy. There is a trial of a gene therapy for the FUS variant that is ongoing. Yet, the introduction of a gene therapy for SOD1 variant ALS has already established that highly targeted therapies can be effective, an important step forward after so many failed treatment trials with nonspecific drugs.

“We are seeing more and more therapies being developed to address specific ALS biology,” said Dr. Fournier, who predicts a pivot toward conceptualizing ALS as an array of pathologies rather than one disorder driven by a single mechanism. More effort is being directed to recognizing phenotypes as well as genotypes. Hopefully, more biomarkers that distinguish between ALS variants will emerge and help in individualizing treatment.

“We are not there yet, but I think many of us in the field see this as a way forward,” she said.
 

Multidisciplinary Care, Symptomatic Management, and Palliative Care Are Still Essential for ALS

Disease-modifying therapies are the ultimate goal in ALS, but Dr. Fournier said that the other side of the equation is multidisciplinary and palliative care. To the extent that almost all ALS therapies only modify the course of disease modestly, palliative care remains the cornerstone of day-to-day care.

“Multidisciplinary and palliative care are not necessarily novel, but they are still critically important. There are clear data to show that multidisciplinary care improves functional status and quality of life, and that this is meaningful to patients,” Dr. Fournier said.

There have been numerous improvements in the areas of multidisciplinary and palliative care, some of which can be credited to advancing technology. In centers of excellence, the multidisciplinary approach has been focused on helping patients sustain a sense of independence and self-worth.

Now robotics, devices, and software are being increasingly employed to extend patient capabilities even in relatively advanced stages of disease, according to Dr. Fournier. As one example, she cited current work in brain-computer interfaces to record electrical activity in the central nervous system to allow patients to communicate even when speech is impaired.

A focus on patient-centered clinical care is appropriate because it is the best current opportunity to improve the lives of patients with ALS. Clinically, this work is very rewarding, according to Dr. Fournier, who described ALS patients overall as generally ”very invested in advocacy and research initiatives and motivated to help others,” Dr. Fournier said.

“The diagnosis can be tough, but there is satisfaction in helping these patients navigate toward an acceptable and meaningful quality of life. They typically give a lot back,” she added.

Overall, there is a sense of progress in ALS, even though it remains a uniformly fatal disease. Dr. Fournier expressed hope that clinical research is reaching a tipping point and an emphasis on targeted treatments after a long list of failed trials over the past 30 years. However, with only one approved therapy modifying an ALS-associated gene, this approach is still in its early stages.

Dr. Fournier has financial relationships with Amylyx, Biogen, Corcept, Denali, Mitsubishi QurAlis, and Tanabe.
 

Suggested Reading

Benatar M et al. Design of a Randomized, Placebo-Controlled, Phase 3 Trial of Tofersen Initiated in Clinically Presymptomatic SOD1 Variant Carriers: the ATLAS Study. Neurotherapeutics. 2022 Jul;19(4):1248-1258. doi: 10.1007/s13311-022-01237-4.

Geronimo A et al. Ten Years of Riluzole Use in a Tertiary ALS Clinic. Muscle Nerve. 2022 Jun;65(6):659-666. doi: 10.1002/mus.27541.

Roggenbuck J et al. Evidence-Based Consensus Guidelines for ALS Genetic Testing and Counseling. Ann Clin Transl Neurol. 2023 Nov;10(11):2074-2091. doi: 10.1002/acn3.51895.

The first therapy targeted at modifying a mutant gene associated with amyotrophic lateral sclerosis (ALS), approved in early 2023, has offered reassurance that the biology of ALS, when known, is targetable. Historically, the disease has been considered a clinical diagnosis, but the progress in identifying molecular mechanisms is permitting ALS to be understood as a biological entity and suggests rationally targeted therapies will be the way forward following the inadequacy of nonselective drugs.

Despite a narrow indication, the only therapy targeted at an ALS-associated gene so far, SOD1 ALS, supports the premise that the biology of ALS can be modified, according to Christina N. Fournier, MD, an associate professor in the Department of Neurology, Emory University, Atlanta, Georgia.

About 15% of ALS Has An Identifiable Genetic Cause

A family history of ALS is present in about 10% of cases. A genetic cause can be identified in approximately 15%. Cases without an identifiable genetic etiology are considered sporadic. So far, the only approved therapy that modifies the function of a gene associated with ALS is tofersen (Qalsody, Biogen), an antisense oligonucleotide. Tofersen inhibits RNA transcription of the superoxide dismutase 1 (SOD1) gene to decrease production of the SOD1 protein.

This first gene therapy for ALS is a breakthrough, but it is indicated for only a small proportion of ALS patients. Even though SOD1 gene mutations represent the second most common genetic cause of ALS after the C90rf72 gene, the proportion of patients who are candidates for tofersen is low. Efficacy is expected only in about 1% of those with familial ALS and 1% of those with sporadic ALS, or about 2% of all patients with ALS.

The evidence of benefit from a treatment with a specific target has provided the basis for concluding that “we are onto something,” Dr. Fournier said. An expert in ALS, she sees reason for excitement about the prospects in treatment with the growing focus on the underlying pathways of disease rather than the downstream consequences.

“The hope is that new gene-targeted therapies will be developed in the future to treat the broader ALS population,” said Dr. Fournier, explaining that the move toward rationally targeted treatments, whether related to gene mutations or independent molecular pathways of ALS progression, has created excitement in the field.

Numerous Disease Processes Are Potentially Targetable

As treatments are developed to address nongenetic molecular processes that contribute to the risk or progression of ALS, such as neuroinflammation or abnormal protein misfolding and aggregation, individualized treatment is likely to become key. Just as not all genetic cases share mutations in the same gene, the key molecular drivers of disease are likely to differ between patients. If so, it is hoped that biomarkers reflective of this underlying biology can be identified to appropriately target treatments.

“The excitement behind the newer targets in clinical trials is based on both basic science and early clinical data that support treatment based on specific drivers of disease,” Dr. Fournier said.

In 2023 and just prior to the FDA approval of tofersen, a set of expert consensus guidelines were published calling for genetic testing to be offered to all patients with ALS. These recommendations suggested that SOD1, C9orf72, FUS, and TARDBP should be included routinely into the panel of genes evaluated, calling for additional genes to be added as they emerge as potential therapeutic targets.

Even before these guidelines were released, genetic testing was already being offered at many centers with expertise in ALS. The rationale was to differentiate ALS with a genetic etiology from that with a nongenetic etiology, as well as to counsel family members when genetic risk was identified, but genetic testing has now assumed new urgency. In addition to the potential for offering a specific treatment for SOD1-related ALS, patients with other genetic forms of disease might be candidates for genetically focused clinical trials.

Genetic testing should be performed as soon as a diagnosis of ALS is made, according to Dr. Fournier. Although not all patients have accepted genetic testing, particularly in the past when there was no immediate clinical gain from establishing the presence of a genetic mutation, she said there is no longer any controversy about clinical relevance.
 

Genetic Testing Is Key to Genetic Therapies

“We do not want to miss the opportunity to treat patients when we have the chance,” said Dr. Fournier, referring to both the likely advantage of an early start of the approved gene therapy as well as the opportunity to participate in a clinical trial with other gene therapies in development.

Prior to the approval of tofersen, riluzole and edaravone had been the only disease-modifying agents in widespread use, but these drugs are nonspecific. There are no established biomarkers for establishing which patients are most likely to benefit.

In the case of riluzole, a pivotal trial conducted 30 years ago showed a survival benefit relative to placebo at 12 months (74% vs. 58%; P = 0.014). In a retrospective study published in 2022 that evaluated survival in a database of 4778 ALS patients of whom 3446 received riluzole, early diagnosis of ALS and prompt treatment with riluzole was associated with longer survival than delayed treatment. The benefit of edaravone has been validated with clinical measures, such as the revised Amyotrophic Lateral Sclerosis Functional Scale (ALSFRS-R).

The retrospective study of riluzole provides the basis for predicting better benefits from disease-modifying therapies if started earlier in the course of ALS. The same premise will be explored with newer therapies that target ALS-associated genes.

Early Treatment Presumed More Effective

“We think that earlier treatment in the course of ALS is probably better for gene therapies as well,” Dr. Fournier said. She cautioned that follow-up is not yet long enough to confirm a survival benefit with tofersen, but she said it is reasonable to anticipate better and longer response when neurologic damage is limited. Citing the effect of gene therapy in spinal muscular atrophy (SMA), where progression is halted if gene therapy is initiated early in life, Dr. Fourier suggested that the emphasis on early treatment stems from the low likelihood for treatments to reverse functional impairments.

“It is conceivable that future treatments might be developed to reverse symptoms, but current drug development is largely aimed at slowing progression,” she explained. Under some circumstances, halting progression has the potential to allow some function to be regained, but as the etiologies of ALS and the pathways of progression are better understood, she believes that all targeted therapy will be started as early as possible to prevent rather than treat neurological damage.

Tofersen, the gene therapy for SOD1-ALS, has provided an opportunity to test the idea that it may be possible to prevent ALS. In a phase 3 trial called ATLAS, unaffected carriers of SOD1 variants that are associated with aggressive disease and high or complete penetrance are enrolled for a run-in phase (Part A) during which participants are followed for a rise in neurofilament light chain (NfL) levels. Based on a previous natural history study called the Pre-Symptomatic Familial ALS (Pre-fALS) study, NfL rises in the serum of unaffected SOD1 carriers prior to phenoconversion. A low NfL is an entry criterion for ATLAS.

ATLAS End Point Is Reduction in Phenoconversion to Clinically Manifest ALS

People in whom NfL rises above a predefined threshold during the run-in stage will be eligible for randomization (Part B) to receive either tofersen or placebo. Efficacy will be measured by comparing the rates of phenoconversion to clinically manifest ALS between those who receive placebo and those who receive tofersen.

Two other groups enrolled in ATLAS will be followed on open-label tofersen. One comprises people who phenoconvert during Part B and the other comprises those who develop ALS during the run-in and therefore are not enrolled in Part B. These patients, forming Parts C and D of the study, provide another set of data to evaluate whether earlier rather than later introduction of therapy provides better outcomes.

“There is a lot of interest and optimism about the trial,” said Dr. Fournier, who praised the trial design and thinks the hypothesis being explored “makes sense.”

Michael Benatar, MD, PhD, professor of neurology and public health, University of Miami School of Medicine, Miami, Florida, is the principal investigator of ATLAS and also leads the Pre-Symptomatic Familial ALS study together with a colleague, Joanne Wuu, Associate Director of Research at the University of Miami ALS Center. The hope from these initiatives, according to Dr. Fournier, is that ATLAS will offer broader learnings beyond just the SOD1 population, providing critical information about the optimal timing of treatment initiation.

The benefit from targeting genes considered causative for ALS is not yet a sure thing. A clinical trial targeting C9orf72, for example, failed to support an approvable therapy. There is a trial of a gene therapy for the FUS variant that is ongoing. Yet, the introduction of a gene therapy for SOD1 variant ALS has already established that highly targeted therapies can be effective, an important step forward after so many failed treatment trials with nonspecific drugs.

“We are seeing more and more therapies being developed to address specific ALS biology,” said Dr. Fournier, who predicts a pivot toward conceptualizing ALS as an array of pathologies rather than one disorder driven by a single mechanism. More effort is being directed to recognizing phenotypes as well as genotypes. Hopefully, more biomarkers that distinguish between ALS variants will emerge and help in individualizing treatment.

“We are not there yet, but I think many of us in the field see this as a way forward,” she said.
 

Multidisciplinary Care, Symptomatic Management, and Palliative Care Are Still Essential for ALS

Disease-modifying therapies are the ultimate goal in ALS, but Dr. Fournier said that the other side of the equation is multidisciplinary and palliative care. To the extent that almost all ALS therapies only modify the course of disease modestly, palliative care remains the cornerstone of day-to-day care.

“Multidisciplinary and palliative care are not necessarily novel, but they are still critically important. There are clear data to show that multidisciplinary care improves functional status and quality of life, and that this is meaningful to patients,” Dr. Fournier said.

There have been numerous improvements in the areas of multidisciplinary and palliative care, some of which can be credited to advancing technology. In centers of excellence, the multidisciplinary approach has been focused on helping patients sustain a sense of independence and self-worth.

Now robotics, devices, and software are being increasingly employed to extend patient capabilities even in relatively advanced stages of disease, according to Dr. Fournier. As one example, she cited current work in brain-computer interfaces to record electrical activity in the central nervous system to allow patients to communicate even when speech is impaired.

A focus on patient-centered clinical care is appropriate because it is the best current opportunity to improve the lives of patients with ALS. Clinically, this work is very rewarding, according to Dr. Fournier, who described ALS patients overall as generally ”very invested in advocacy and research initiatives and motivated to help others,” Dr. Fournier said.

“The diagnosis can be tough, but there is satisfaction in helping these patients navigate toward an acceptable and meaningful quality of life. They typically give a lot back,” she added.

Overall, there is a sense of progress in ALS, even though it remains a uniformly fatal disease. Dr. Fournier expressed hope that clinical research is reaching a tipping point and an emphasis on targeted treatments after a long list of failed trials over the past 30 years. However, with only one approved therapy modifying an ALS-associated gene, this approach is still in its early stages.

Dr. Fournier has financial relationships with Amylyx, Biogen, Corcept, Denali, Mitsubishi QurAlis, and Tanabe.
 

Suggested Reading

Benatar M et al. Design of a Randomized, Placebo-Controlled, Phase 3 Trial of Tofersen Initiated in Clinically Presymptomatic SOD1 Variant Carriers: the ATLAS Study. Neurotherapeutics. 2022 Jul;19(4):1248-1258. doi: 10.1007/s13311-022-01237-4.

Geronimo A et al. Ten Years of Riluzole Use in a Tertiary ALS Clinic. Muscle Nerve. 2022 Jun;65(6):659-666. doi: 10.1002/mus.27541.

Roggenbuck J et al. Evidence-Based Consensus Guidelines for ALS Genetic Testing and Counseling. Ann Clin Transl Neurol. 2023 Nov;10(11):2074-2091. doi: 10.1002/acn3.51895.

COPENHAGEN — Multiple Sclerosis (MS) experts are recommending updates to the 2017 McDonald diagnostic criteria in order to make diagnosis easier, faster, and more accurate.

Among its recommendations, the expert panel advises incorporating optic nerve imaging for diagnosis and applying stricter criteria for older patients. In addition, it proposes that radiologically isolated syndrome (RIS) may be diagnosed as MS in certain cases and that disease dissemination in time (DIT) should no longer be required. 

The proposed criteria changes were presented at the 2024 ECTRIMS annual meeting.

Committee member Xavier Montalban, MD, PhD, from the Department of Neurology and the MS Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona, Spain, told conference attendees that MS is a diagnosis of exclusion.

Brain and spinal cord MRI remains the most useful paraclinical test to diagnose the disease, he said, and an abnormal MRI showing typical lesions is required.

Dr. Montalban noted that optic neuritis is the first manifestation of MS in 25%-35% of cases with clinically isolated syndrome (CIS) — one of the four MS disease courses.

Therefore, he said, the panel is recommending that the optic nerve serve as the “fifth topography” or a fifth anatomical location to demonstrate dissemination in space (DIS) if there’s no better explanation for optic nerve pathology, he said. 

Considerable evidence supports the minimal threshold of at least one lesion in at least two of the five topographies after including the optic nerve, he added.
 

DIS Alone Sufficient?

The panel also concluded that demonstrating DIS alone, without the need for DIT or positive cerebrospinal fluid (CSF), may be sufficient for an MS diagnosis. Currently, both DIS and DIT are required.

The committee broached the topic of RIS, which is identified by the incidental discovery of central nervous system (CNS) white matter T2-weighted hyperintense foci on MRI. These hyperintense foci demonstrate morphological and spatial characteristics highly typical of MS but without clinical symptomatology related to inflammatory demyelination.

Dr. Montalban noted that most patients with RIS will develop MS within 10 years. For these individuals, the panel concluded that the following criteria are sufficient for an MS diagnosis: fulfilling both DIS and DIT; fulfilling DIS and the presence of oligoclonal bands (OCBs) in the cerebrospinal fluid; or fulfilling DIS along with six or more central vein signs (CVS).

The panel proposes the addition of CVS and paramagnetic rim lesions, which are MRI markers of chronic active lesions, as optional tools for MS diagnosis in certain situations. Demonstration of CVS by MRI can increase specificity, said Dr. Montalban.

Evidence also suggests that kappa free light chains (KFLCs) could serve as a valid, simpler, and rater-independent alternative to detecting OCBs, he added. Because KFLCs are interchangeable with OCBs, they can be used in place of OCBs for diagnosing MS through CSF analysis.
 

Stricter Criteria

The panel is also calling for stricter criteria for confirming an MS diagnosis in those over age 50 or individuals with headache or vascular disorders. In such patients, they strongly recommend additional features such as a spinal cord lesion, positive CSF, and CVS select 6 (six positive lesions).

The panel is also recommending laboratory tests (MOG-IgG Ab) to confirm a diagnosis in children and adolescents. Dr. Montalban noted the presence of CVS in about 50% of T2 lesions strongly suggests MS in this population.

Primary progressive MS (PPMS) requires evidence of clinical progression over at least 12 months. The committee determined that the same criteria for relapsing-remitting MS could be used for PPMS. 

Having a single, unified framework of diagnostic criteria will be “very useful,” said Dr. Montalban.

During the same meeting session, Marcello Moccia, MD, PhD, University College London (UCL) Queen Square Institute of Neurology, Faculty of Brain Sciences, London, England, presented examples of patients for whom the revised criteria could be beneficial. 

These examples help illustrate how using the new criteria, for example optic nerve imaging, could lead to earlier diagnoses, and, in some cases, easier diagnoses, possibly with less CSF, he said. It could also lead to fewer misdiagnoses, he added, thanks to high-specificity tools.

Implementing the new criteria could offer greater flexibility and reduce complexity, Dr. Moccia concluded, adding that not every patient with suspected MS requires exhaustive testing.

The committee’s next steps will include consulting with the wider MS community and preparing the information for publication, said Dr. Montalban.

Commenting on the proposals, Bruce Bebo, executive vice president of research, National MS Society, agreed the proposed changes to the McDonald Criteria will make diagnosing MS “faster and easier.”

“Importantly, we are providing guidance that is inclusive — how to confirm diagnoses in children, or in people over the age of 50,” said Dr. Bebo. “We’re bringing the latest research and imaging technology to the forefront, to help people with MS get treatment faster, so they can live their best lives.”

Dr. Montalban’s institution has received compensation for lecture honoraria and travel expenses, participation in scientific meetings, clinical trial steering committee membership, or clinical advisory board participation in recent years from AbbVie, Actelion, Alexion, Bial PD, Biogen, Bristol Myers Squibb/Celgene, EMD Serona, Genzyme, Hoffmann-La Roche, Immunic Therapeutics, Janssen Pharmaceuticals, MedDay, Merck, Mylan, Nervgen, Neuraxpharm, Novartis, PeerVoice, Samsung-Biosys Sandoz Sanofi-Genzyme, Teva Pharmaceuticals, TG Therapeutics, EXCEMED, ECTRIMS, MSIF, and NMSS or any of their affiliates. Dr. Moccia reports receiving a salary from University of Naples, Policlinico University Hospital (Naples) and Neurology (US); research grants from MUR PNRR Extended Partnership, ECTRIMS-MAGNIMS, UK MS Society, and Merck; honoraria from AbbVie, Biogen, BMS Celgene, Ipsen, Jansen, Merck, Novartis, Roche, and Sanofi-Genzyme. 

A version of this article appeared on Medscape.com.

COPENHAGEN — Multiple Sclerosis (MS) experts are recommending updates to the 2017 McDonald diagnostic criteria in order to make diagnosis easier, faster, and more accurate.

Among its recommendations, the expert panel advises incorporating optic nerve imaging for diagnosis and applying stricter criteria for older patients. In addition, it proposes that radiologically isolated syndrome (RIS) may be diagnosed as MS in certain cases and that disease dissemination in time (DIT) should no longer be required. 

The proposed criteria changes were presented at the 2024 ECTRIMS annual meeting.

Committee member Xavier Montalban, MD, PhD, from the Department of Neurology and the MS Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona, Spain, told conference attendees that MS is a diagnosis of exclusion.

Brain and spinal cord MRI remains the most useful paraclinical test to diagnose the disease, he said, and an abnormal MRI showing typical lesions is required.

Dr. Montalban noted that optic neuritis is the first manifestation of MS in 25%-35% of cases with clinically isolated syndrome (CIS) — one of the four MS disease courses.

Therefore, he said, the panel is recommending that the optic nerve serve as the “fifth topography” or a fifth anatomical location to demonstrate dissemination in space (DIS) if there’s no better explanation for optic nerve pathology, he said. 

Considerable evidence supports the minimal threshold of at least one lesion in at least two of the five topographies after including the optic nerve, he added.
 

DIS Alone Sufficient?

The panel also concluded that demonstrating DIS alone, without the need for DIT or positive cerebrospinal fluid (CSF), may be sufficient for an MS diagnosis. Currently, both DIS and DIT are required.

The committee broached the topic of RIS, which is identified by the incidental discovery of central nervous system (CNS) white matter T2-weighted hyperintense foci on MRI. These hyperintense foci demonstrate morphological and spatial characteristics highly typical of MS but without clinical symptomatology related to inflammatory demyelination.

Dr. Montalban noted that most patients with RIS will develop MS within 10 years. For these individuals, the panel concluded that the following criteria are sufficient for an MS diagnosis: fulfilling both DIS and DIT; fulfilling DIS and the presence of oligoclonal bands (OCBs) in the cerebrospinal fluid; or fulfilling DIS along with six or more central vein signs (CVS).

The panel proposes the addition of CVS and paramagnetic rim lesions, which are MRI markers of chronic active lesions, as optional tools for MS diagnosis in certain situations. Demonstration of CVS by MRI can increase specificity, said Dr. Montalban.

Evidence also suggests that kappa free light chains (KFLCs) could serve as a valid, simpler, and rater-independent alternative to detecting OCBs, he added. Because KFLCs are interchangeable with OCBs, they can be used in place of OCBs for diagnosing MS through CSF analysis.
 

Stricter Criteria

The panel is also calling for stricter criteria for confirming an MS diagnosis in those over age 50 or individuals with headache or vascular disorders. In such patients, they strongly recommend additional features such as a spinal cord lesion, positive CSF, and CVS select 6 (six positive lesions).

The panel is also recommending laboratory tests (MOG-IgG Ab) to confirm a diagnosis in children and adolescents. Dr. Montalban noted the presence of CVS in about 50% of T2 lesions strongly suggests MS in this population.

Primary progressive MS (PPMS) requires evidence of clinical progression over at least 12 months. The committee determined that the same criteria for relapsing-remitting MS could be used for PPMS. 

Having a single, unified framework of diagnostic criteria will be “very useful,” said Dr. Montalban.

During the same meeting session, Marcello Moccia, MD, PhD, University College London (UCL) Queen Square Institute of Neurology, Faculty of Brain Sciences, London, England, presented examples of patients for whom the revised criteria could be beneficial. 

These examples help illustrate how using the new criteria, for example optic nerve imaging, could lead to earlier diagnoses, and, in some cases, easier diagnoses, possibly with less CSF, he said. It could also lead to fewer misdiagnoses, he added, thanks to high-specificity tools.

Implementing the new criteria could offer greater flexibility and reduce complexity, Dr. Moccia concluded, adding that not every patient with suspected MS requires exhaustive testing.

The committee’s next steps will include consulting with the wider MS community and preparing the information for publication, said Dr. Montalban.

Commenting on the proposals, Bruce Bebo, executive vice president of research, National MS Society, agreed the proposed changes to the McDonald Criteria will make diagnosing MS “faster and easier.”

“Importantly, we are providing guidance that is inclusive — how to confirm diagnoses in children, or in people over the age of 50,” said Dr. Bebo. “We’re bringing the latest research and imaging technology to the forefront, to help people with MS get treatment faster, so they can live their best lives.”

Dr. Montalban’s institution has received compensation for lecture honoraria and travel expenses, participation in scientific meetings, clinical trial steering committee membership, or clinical advisory board participation in recent years from AbbVie, Actelion, Alexion, Bial PD, Biogen, Bristol Myers Squibb/Celgene, EMD Serona, Genzyme, Hoffmann-La Roche, Immunic Therapeutics, Janssen Pharmaceuticals, MedDay, Merck, Mylan, Nervgen, Neuraxpharm, Novartis, PeerVoice, Samsung-Biosys Sandoz Sanofi-Genzyme, Teva Pharmaceuticals, TG Therapeutics, EXCEMED, ECTRIMS, MSIF, and NMSS or any of their affiliates. Dr. Moccia reports receiving a salary from University of Naples, Policlinico University Hospital (Naples) and Neurology (US); research grants from MUR PNRR Extended Partnership, ECTRIMS-MAGNIMS, UK MS Society, and Merck; honoraria from AbbVie, Biogen, BMS Celgene, Ipsen, Jansen, Merck, Novartis, Roche, and Sanofi-Genzyme. 

A version of this article appeared on Medscape.com.

COPENHAGEN — Multiple Sclerosis (MS) experts are recommending updates to the 2017 McDonald diagnostic criteria in order to make diagnosis easier, faster, and more accurate.

Among its recommendations, the expert panel advises incorporating optic nerve imaging for diagnosis and applying stricter criteria for older patients. In addition, it proposes that radiologically isolated syndrome (RIS) may be diagnosed as MS in certain cases and that disease dissemination in time (DIT) should no longer be required. 

The proposed criteria changes were presented at the 2024 ECTRIMS annual meeting.

Committee member Xavier Montalban, MD, PhD, from the Department of Neurology and the MS Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona, Spain, told conference attendees that MS is a diagnosis of exclusion.

Brain and spinal cord MRI remains the most useful paraclinical test to diagnose the disease, he said, and an abnormal MRI showing typical lesions is required.

Dr. Montalban noted that optic neuritis is the first manifestation of MS in 25%-35% of cases with clinically isolated syndrome (CIS) — one of the four MS disease courses.

Therefore, he said, the panel is recommending that the optic nerve serve as the “fifth topography” or a fifth anatomical location to demonstrate dissemination in space (DIS) if there’s no better explanation for optic nerve pathology, he said. 

Considerable evidence supports the minimal threshold of at least one lesion in at least two of the five topographies after including the optic nerve, he added.
 

DIS Alone Sufficient?

The panel also concluded that demonstrating DIS alone, without the need for DIT or positive cerebrospinal fluid (CSF), may be sufficient for an MS diagnosis. Currently, both DIS and DIT are required.

The committee broached the topic of RIS, which is identified by the incidental discovery of central nervous system (CNS) white matter T2-weighted hyperintense foci on MRI. These hyperintense foci demonstrate morphological and spatial characteristics highly typical of MS but without clinical symptomatology related to inflammatory demyelination.

Dr. Montalban noted that most patients with RIS will develop MS within 10 years. For these individuals, the panel concluded that the following criteria are sufficient for an MS diagnosis: fulfilling both DIS and DIT; fulfilling DIS and the presence of oligoclonal bands (OCBs) in the cerebrospinal fluid; or fulfilling DIS along with six or more central vein signs (CVS).

The panel proposes the addition of CVS and paramagnetic rim lesions, which are MRI markers of chronic active lesions, as optional tools for MS diagnosis in certain situations. Demonstration of CVS by MRI can increase specificity, said Dr. Montalban.

Evidence also suggests that kappa free light chains (KFLCs) could serve as a valid, simpler, and rater-independent alternative to detecting OCBs, he added. Because KFLCs are interchangeable with OCBs, they can be used in place of OCBs for diagnosing MS through CSF analysis.
 

Stricter Criteria

The panel is also calling for stricter criteria for confirming an MS diagnosis in those over age 50 or individuals with headache or vascular disorders. In such patients, they strongly recommend additional features such as a spinal cord lesion, positive CSF, and CVS select 6 (six positive lesions).

The panel is also recommending laboratory tests (MOG-IgG Ab) to confirm a diagnosis in children and adolescents. Dr. Montalban noted the presence of CVS in about 50% of T2 lesions strongly suggests MS in this population.

Primary progressive MS (PPMS) requires evidence of clinical progression over at least 12 months. The committee determined that the same criteria for relapsing-remitting MS could be used for PPMS. 

Having a single, unified framework of diagnostic criteria will be “very useful,” said Dr. Montalban.

During the same meeting session, Marcello Moccia, MD, PhD, University College London (UCL) Queen Square Institute of Neurology, Faculty of Brain Sciences, London, England, presented examples of patients for whom the revised criteria could be beneficial. 

These examples help illustrate how using the new criteria, for example optic nerve imaging, could lead to earlier diagnoses, and, in some cases, easier diagnoses, possibly with less CSF, he said. It could also lead to fewer misdiagnoses, he added, thanks to high-specificity tools.

Implementing the new criteria could offer greater flexibility and reduce complexity, Dr. Moccia concluded, adding that not every patient with suspected MS requires exhaustive testing.

The committee’s next steps will include consulting with the wider MS community and preparing the information for publication, said Dr. Montalban.

Commenting on the proposals, Bruce Bebo, executive vice president of research, National MS Society, agreed the proposed changes to the McDonald Criteria will make diagnosing MS “faster and easier.”

“Importantly, we are providing guidance that is inclusive — how to confirm diagnoses in children, or in people over the age of 50,” said Dr. Bebo. “We’re bringing the latest research and imaging technology to the forefront, to help people with MS get treatment faster, so they can live their best lives.”

Dr. Montalban’s institution has received compensation for lecture honoraria and travel expenses, participation in scientific meetings, clinical trial steering committee membership, or clinical advisory board participation in recent years from AbbVie, Actelion, Alexion, Bial PD, Biogen, Bristol Myers Squibb/Celgene, EMD Serona, Genzyme, Hoffmann-La Roche, Immunic Therapeutics, Janssen Pharmaceuticals, MedDay, Merck, Mylan, Nervgen, Neuraxpharm, Novartis, PeerVoice, Samsung-Biosys Sandoz Sanofi-Genzyme, Teva Pharmaceuticals, TG Therapeutics, EXCEMED, ECTRIMS, MSIF, and NMSS or any of their affiliates. Dr. Moccia reports receiving a salary from University of Naples, Policlinico University Hospital (Naples) and Neurology (US); research grants from MUR PNRR Extended Partnership, ECTRIMS-MAGNIMS, UK MS Society, and Merck; honoraria from AbbVie, Biogen, BMS Celgene, Ipsen, Jansen, Merck, Novartis, Roche, and Sanofi-Genzyme. 

A version of this article appeared on Medscape.com.

COPENHAGEN — A higher cumulative genetic burden for depression is associated with an increased risk for relapse and worsening disability in people with multiple sclerosis (MS), early results of a new study showed.

Unlike the previous research, the current analysis used polygenic risk scores for depression, which summarize the estimated effect of genetic variants to determine the potential association with MS disease activity, so results are less likely to be explained by reverse causality.

This study increases awareness of the link between depression and MS, said study investigator Kaarina Kowalec, PhD, assistant professor, College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada. “We’re starting to understand how depression affects relapses and disability progression in MS,” she said.

The findings were presented at the 2024 ECTRIMS annual meeting.
 

Common Comorbidity

Depression is a common comorbidity in patients with MS and is associated with increased relapse and disability progression. Depression risk is partly polygenic in nature, involving numerous common genetic variants, said Dr. Kowalec.

The case-control study included 3420 relapsing-onset MS cases of European ancestry from four existing cohorts in three countries.

The Canadian cohort included those enrolled in a prospective longitudinal study of psychiatric comorbidity in chronic immune-mediated inflammatory disease (IMID), including MS; the Swedish cohort was an MS registry (SSReg) that encompasses 64 MS clinics (the cohort was split into two groups); and the US cohort was enrolled in a clinical trial of combined therapy with interferon and glatiramer acetate (CombiRx) in patients with MS.

The median follow-up in these cohorts ranged from 3 to 5 years.

Not surprisingly, most participants were women (from 71% in one of the Swedish cohorts to 83% in the Canadian cohort), and the age at MS onset ranged from 29 years in the Canadian cohort to 35 years in one of the Swedish cohorts.

The median baseline Expanded Disability Status Scale (EDSS) score was higher in the Canadian cohort (3.5) than in the Swedish (1.5) and US (2.0) cohorts, “reflective of the Canadian cohort being slightly more progressed,” said Dr. Kowalec.
 

Inherited Variants

To measure depression heritability, researchers generated a polygenic risk score in whole-genome imputed genotypes. The score reflects the number of inherited common genetic variants, weighted by effect sizes.

Researchers investigated the association between depression polygenic risk scores (top 20% vs. bottom 80%) with annualized relapse rate and worsening disability in MS measured by the rate of change in EDSS score. In the US cohort, they also explored the association between depression polygenic risk scores and time to relapse and confirmed EDSS worsening.

Covariates included use of disease-modifying therapy, age, sex, and the first five genetic ancestry principal components. The latter was done to capture residual stratification by genetic ancestry, although Dr. Kowalec stressed analyses were done only in those of European ancestry.

Investigators found a higher depression polygenic risk score was associated with relapse risk (incident rate ratio, 1.23; 95% CI, 1.01-1.49).

“Essentially, for every one standard deviation increase in the depression polygenic score, we found a significant increased hazard of 23% for experiencing a relapse over the follow-up period,” said Dr. Kowalec, who is also affiliated with the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

She noted the Canadian cohort did not have many relapses, while the US and Swedish cohorts “had an increased rate.”

Other analyses examined the risk of having a relapse or worsening disability. Every one SD increase in the depression polygenic risk score was significantly associated with a 2.2 greater risk of experiencing relapse (hazard ratio [HR], 2.20; 95% CI, 1.35-3.60) and a 51% increased risk for confirmed EDSS progression (HR, 1.51; 95% CI, 1.03-2.22).
 

‘An Ideal Marker’

Use of polygenetic risk scores reduces the possibility of reverse causation, noted Dr. Kowalec. “These markers are fixed at birth and don’t change over your lifespan, so they’re really an ideal marker.”

The results suggest polygenetic risk scores represent a potential biomarker for risk stratification in people with MS, said Dr. Kowalec. Although depression polygenic risk scores are not currently available in clinical practice, “I would hope this would change in the next 3-4 years,” she said.

Asked by a delegate if confounding by a third variable is possible, Dr. Kowalec said because genetic markers don’t change over time, there is a hint that the direction is causal and that depression is driving the outcome. However, she added, further confirmation is needed.

Dr. Kowalec noted that there were no data on antidepressant use but noted that about half of the Canadian and US cohorts — and likely the same number in the Swedish cohorts — self-reported depression.

A limitation of the study was that it included only participants of European ancestry.
 

Clinical Implications Unclear

Commenting on the research, Lauren Gluck, MD, program director, Montefiore Multiple Sclerosis Center, Bronx, New York, described the study as “fascinating” but noted that it’s unclear how to use this new information in clinical practice.

“Clinicians frequently ask people with MS about mood symptoms and offer interventions like antidepressants and referrals to therapists. However, genetic testing is not routine, so we don’t yet know who to target based on these data.”

Preexisting depression or more severe depression could be viewed as a “red flag” for risk for more disease activity in the future, she said.

“This could encourage clinicians to use more highly effective therapy in these patients, similar to our strategies for people with MS with frequent attacks and more disease burden on MRIs.”

The study received support from the Consortium of Multiple Sclerosis Centers and the Congressionally Directed Medical Research Programs, Department of Defense.

Dr. Kowalec reported no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

COPENHAGEN — A higher cumulative genetic burden for depression is associated with an increased risk for relapse and worsening disability in people with multiple sclerosis (MS), early results of a new study showed.

Unlike the previous research, the current analysis used polygenic risk scores for depression, which summarize the estimated effect of genetic variants to determine the potential association with MS disease activity, so results are less likely to be explained by reverse causality.

This study increases awareness of the link between depression and MS, said study investigator Kaarina Kowalec, PhD, assistant professor, College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada. “We’re starting to understand how depression affects relapses and disability progression in MS,” she said.

The findings were presented at the 2024 ECTRIMS annual meeting.
 

Common Comorbidity

Depression is a common comorbidity in patients with MS and is associated with increased relapse and disability progression. Depression risk is partly polygenic in nature, involving numerous common genetic variants, said Dr. Kowalec.

The case-control study included 3420 relapsing-onset MS cases of European ancestry from four existing cohorts in three countries.

The Canadian cohort included those enrolled in a prospective longitudinal study of psychiatric comorbidity in chronic immune-mediated inflammatory disease (IMID), including MS; the Swedish cohort was an MS registry (SSReg) that encompasses 64 MS clinics (the cohort was split into two groups); and the US cohort was enrolled in a clinical trial of combined therapy with interferon and glatiramer acetate (CombiRx) in patients with MS.

The median follow-up in these cohorts ranged from 3 to 5 years.

Not surprisingly, most participants were women (from 71% in one of the Swedish cohorts to 83% in the Canadian cohort), and the age at MS onset ranged from 29 years in the Canadian cohort to 35 years in one of the Swedish cohorts.

The median baseline Expanded Disability Status Scale (EDSS) score was higher in the Canadian cohort (3.5) than in the Swedish (1.5) and US (2.0) cohorts, “reflective of the Canadian cohort being slightly more progressed,” said Dr. Kowalec.
 

Inherited Variants

To measure depression heritability, researchers generated a polygenic risk score in whole-genome imputed genotypes. The score reflects the number of inherited common genetic variants, weighted by effect sizes.

Researchers investigated the association between depression polygenic risk scores (top 20% vs. bottom 80%) with annualized relapse rate and worsening disability in MS measured by the rate of change in EDSS score. In the US cohort, they also explored the association between depression polygenic risk scores and time to relapse and confirmed EDSS worsening.

Covariates included use of disease-modifying therapy, age, sex, and the first five genetic ancestry principal components. The latter was done to capture residual stratification by genetic ancestry, although Dr. Kowalec stressed analyses were done only in those of European ancestry.

Investigators found a higher depression polygenic risk score was associated with relapse risk (incident rate ratio, 1.23; 95% CI, 1.01-1.49).

“Essentially, for every one standard deviation increase in the depression polygenic score, we found a significant increased hazard of 23% for experiencing a relapse over the follow-up period,” said Dr. Kowalec, who is also affiliated with the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

She noted the Canadian cohort did not have many relapses, while the US and Swedish cohorts “had an increased rate.”

Other analyses examined the risk of having a relapse or worsening disability. Every one SD increase in the depression polygenic risk score was significantly associated with a 2.2 greater risk of experiencing relapse (hazard ratio [HR], 2.20; 95% CI, 1.35-3.60) and a 51% increased risk for confirmed EDSS progression (HR, 1.51; 95% CI, 1.03-2.22).
 

‘An Ideal Marker’

Use of polygenetic risk scores reduces the possibility of reverse causation, noted Dr. Kowalec. “These markers are fixed at birth and don’t change over your lifespan, so they’re really an ideal marker.”

The results suggest polygenetic risk scores represent a potential biomarker for risk stratification in people with MS, said Dr. Kowalec. Although depression polygenic risk scores are not currently available in clinical practice, “I would hope this would change in the next 3-4 years,” she said.

Asked by a delegate if confounding by a third variable is possible, Dr. Kowalec said because genetic markers don’t change over time, there is a hint that the direction is causal and that depression is driving the outcome. However, she added, further confirmation is needed.

Dr. Kowalec noted that there were no data on antidepressant use but noted that about half of the Canadian and US cohorts — and likely the same number in the Swedish cohorts — self-reported depression.

A limitation of the study was that it included only participants of European ancestry.
 

Clinical Implications Unclear

Commenting on the research, Lauren Gluck, MD, program director, Montefiore Multiple Sclerosis Center, Bronx, New York, described the study as “fascinating” but noted that it’s unclear how to use this new information in clinical practice.

“Clinicians frequently ask people with MS about mood symptoms and offer interventions like antidepressants and referrals to therapists. However, genetic testing is not routine, so we don’t yet know who to target based on these data.”

Preexisting depression or more severe depression could be viewed as a “red flag” for risk for more disease activity in the future, she said.

“This could encourage clinicians to use more highly effective therapy in these patients, similar to our strategies for people with MS with frequent attacks and more disease burden on MRIs.”

The study received support from the Consortium of Multiple Sclerosis Centers and the Congressionally Directed Medical Research Programs, Department of Defense.

Dr. Kowalec reported no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

COPENHAGEN — A higher cumulative genetic burden for depression is associated with an increased risk for relapse and worsening disability in people with multiple sclerosis (MS), early results of a new study showed.

Unlike the previous research, the current analysis used polygenic risk scores for depression, which summarize the estimated effect of genetic variants to determine the potential association with MS disease activity, so results are less likely to be explained by reverse causality.

This study increases awareness of the link between depression and MS, said study investigator Kaarina Kowalec, PhD, assistant professor, College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada. “We’re starting to understand how depression affects relapses and disability progression in MS,” she said.

The findings were presented at the 2024 ECTRIMS annual meeting.
 

Common Comorbidity

Depression is a common comorbidity in patients with MS and is associated with increased relapse and disability progression. Depression risk is partly polygenic in nature, involving numerous common genetic variants, said Dr. Kowalec.

The case-control study included 3420 relapsing-onset MS cases of European ancestry from four existing cohorts in three countries.

The Canadian cohort included those enrolled in a prospective longitudinal study of psychiatric comorbidity in chronic immune-mediated inflammatory disease (IMID), including MS; the Swedish cohort was an MS registry (SSReg) that encompasses 64 MS clinics (the cohort was split into two groups); and the US cohort was enrolled in a clinical trial of combined therapy with interferon and glatiramer acetate (CombiRx) in patients with MS.

The median follow-up in these cohorts ranged from 3 to 5 years.

Not surprisingly, most participants were women (from 71% in one of the Swedish cohorts to 83% in the Canadian cohort), and the age at MS onset ranged from 29 years in the Canadian cohort to 35 years in one of the Swedish cohorts.

The median baseline Expanded Disability Status Scale (EDSS) score was higher in the Canadian cohort (3.5) than in the Swedish (1.5) and US (2.0) cohorts, “reflective of the Canadian cohort being slightly more progressed,” said Dr. Kowalec.
 

Inherited Variants

To measure depression heritability, researchers generated a polygenic risk score in whole-genome imputed genotypes. The score reflects the number of inherited common genetic variants, weighted by effect sizes.

Researchers investigated the association between depression polygenic risk scores (top 20% vs. bottom 80%) with annualized relapse rate and worsening disability in MS measured by the rate of change in EDSS score. In the US cohort, they also explored the association between depression polygenic risk scores and time to relapse and confirmed EDSS worsening.

Covariates included use of disease-modifying therapy, age, sex, and the first five genetic ancestry principal components. The latter was done to capture residual stratification by genetic ancestry, although Dr. Kowalec stressed analyses were done only in those of European ancestry.

Investigators found a higher depression polygenic risk score was associated with relapse risk (incident rate ratio, 1.23; 95% CI, 1.01-1.49).

“Essentially, for every one standard deviation increase in the depression polygenic score, we found a significant increased hazard of 23% for experiencing a relapse over the follow-up period,” said Dr. Kowalec, who is also affiliated with the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

She noted the Canadian cohort did not have many relapses, while the US and Swedish cohorts “had an increased rate.”

Other analyses examined the risk of having a relapse or worsening disability. Every one SD increase in the depression polygenic risk score was significantly associated with a 2.2 greater risk of experiencing relapse (hazard ratio [HR], 2.20; 95% CI, 1.35-3.60) and a 51% increased risk for confirmed EDSS progression (HR, 1.51; 95% CI, 1.03-2.22).
 

‘An Ideal Marker’

Use of polygenetic risk scores reduces the possibility of reverse causation, noted Dr. Kowalec. “These markers are fixed at birth and don’t change over your lifespan, so they’re really an ideal marker.”

The results suggest polygenetic risk scores represent a potential biomarker for risk stratification in people with MS, said Dr. Kowalec. Although depression polygenic risk scores are not currently available in clinical practice, “I would hope this would change in the next 3-4 years,” she said.

Asked by a delegate if confounding by a third variable is possible, Dr. Kowalec said because genetic markers don’t change over time, there is a hint that the direction is causal and that depression is driving the outcome. However, she added, further confirmation is needed.

Dr. Kowalec noted that there were no data on antidepressant use but noted that about half of the Canadian and US cohorts — and likely the same number in the Swedish cohorts — self-reported depression.

A limitation of the study was that it included only participants of European ancestry.
 

Clinical Implications Unclear

Commenting on the research, Lauren Gluck, MD, program director, Montefiore Multiple Sclerosis Center, Bronx, New York, described the study as “fascinating” but noted that it’s unclear how to use this new information in clinical practice.

“Clinicians frequently ask people with MS about mood symptoms and offer interventions like antidepressants and referrals to therapists. However, genetic testing is not routine, so we don’t yet know who to target based on these data.”

Preexisting depression or more severe depression could be viewed as a “red flag” for risk for more disease activity in the future, she said.

“This could encourage clinicians to use more highly effective therapy in these patients, similar to our strategies for people with MS with frequent attacks and more disease burden on MRIs.”

The study received support from the Consortium of Multiple Sclerosis Centers and the Congressionally Directed Medical Research Programs, Department of Defense.

Dr. Kowalec reported no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

As a psychiatrist specializing in eating disorders, Kim Dennis, MD, has seen firsthand the complex relationship between obesity treatment and mental health in adolescents.

Now, with the rising popularity of medications like Ozempic for weight loss, she fears she will care for more teens with eating disorders who are seeking glucagon-like peptide 1 (GLP-1) agonists or who have developed a disorder while taking them.

“We haven’t seen patients yet, but I’m sure they are on their way,” said Dr. Dennis, a clinical assistant professor in the Department of Psychiatry at the University of Illinois College of Medicine in Chicago. She is also the cofounder and chief medical officer of SunCloud Health, an outpatient eating disorder treatment center in Illinois.

Dr. Dennis’ concerns reflect a growing unease among eating disorder specialists as obesity medications gain traction for adolescent use. A recent study published in JAMA Pediatrics showed nearly 80% of teens in treatment for obesity reported symptoms of disordered eating at the outset of an intervention. These included signs of binge eating and loss of control.

The randomized clinical trial, conducted from 2018 to 2023, examined 141 adolescents with obesity undergoing interventions like low-energy diets or intermittent energy restriction. Almost half scored as having risk for an undiagnosed eating disorder, as defined by the Eating Disorder Examination Questionnaire (EDE-Q).

At the end of the intervention, many teens continued to have symptoms of disordered eating, while a smaller group was newly scored as having a risk for an eating disorder.
 

Weight Loss and Eating Disorders: A Balancing Act

The findings illuminate a significant challenge for pediatricians and primary care clinicians: Balancing effective weight management with the risk of exacerbating or triggering eating disorders, said Hiba Jebeile, PhD, a research dietitian at The Children’s Hospital at Westmead in Australia, and the study’s lead author. Adding weight loss medication on top of the equation can further complicate care.

“It is helpful for obesity and eating disorder services to work together, with clear referral pathways, to manage these adolescents,” Dr. Jebeile said.

The US Food and Drug Administration approved semaglutide for weight loss in adolescents aged 12-17 years in December 2020. One study found that the number of adolescents prescribed GLP-1 receptor agonists (GLP-1 RAs) for type 2 diabetes and weight management rose from 8722 to 60,567 between 2020 and 2023 — a nearly sevenfold increase.

“The number of adolescents taking these medications is going up because they work,” said Suzanne Cuda, MD, medical director of Alamo City Healthy Kids and Families, a medical weight management clinic in San Antonio. The medications have been shown to treat type 2 diabetes, lower blood pressure, and reduce the risk for cardiovascular diseases.

“The younger you are, the better the outcome,” Dr. Cuda said.

How GLP-1 agonists may affect adolescents in the long run is not yet clear. Existing studies on GLP-1 medications in patients with eating disorders have shown mixed results. Some studies indicate that the drugs decrease binge episodes for those with binge eating disorder or bulimia nervosa. However, these studies had small sample sizes and measured only short-term effects, leaving long-term outcomes and risks unknown.

Traditional treatments for eating disorders emphasize regular eating patterns, body acceptance, addressing weight stigma, and improving attunement to hunger and fullness cues — approaches that may conflict with the effects of GLP-1 agonists. These drugs suppress appetite, alter metabolic signals, and may unintentionally reinforce weight loss as a primary goal, creating a potential disconnect between the aims of recovery from eating disorders and the biologic effects of the medication, experts said.

Dr. Cuda said she has cared for adolescents with diagnosed eating disorders in her practice who are seeking GLP-1 agonists. She said she first works with patients to treat the underlying disorder before prescribing medication.

“One of the concerns is the extreme reductions in calories that could be induced by GLP-1 RA in children and adolescents,” she said. Unlike adults, adolescents use caloric energy not just for physical activity but also for growing and developing, she said.

“They can’t catch up on that growth and development,” she added.
 

Advice for Screening and Monitoring

The National Eating Disorders Association raised concerns about the potential misuse of these medications and their potential to exacerbate eating disorder behaviors in people who are already at a higher risk of developing one of the conditions, including those with existing mental health disorders, stress, who have already dieted, and who have experienced weight-centric bullying.

Clinicians should be on the lookout for patients seeking GLP-1s who present with symptoms of an eating disorder that may be less apparent, such as picky eating, insomnia or difficulty sleeping, or, for girls, irregular menstrual periods, Dr. Dennis said. These patients may be more likely to go undiagnosed or misdiagnosed. Research also suggests that people of color are less likely to be diagnosed or receive specialty care for eating disorders.

Discussions between patients and clinicians about obesity treatment prior to prescribing provide a crucial opportunity to screen and monitor for disordered eating, which Dr. Dennis said does not universally occur currently.

Dr. Dennis recommended initial assessments using validated screening tools like the EDE-Q and the Center for Epidemiologic Studies Depression Scale Revised, 10-Item Version.

Ongoing monitoring throughout treatment is essential, with initial monthly check-ins that include dietary counseling to detect subtle changes in eating behaviors or attitudes toward food and body image, Dr. Cuda said.

The Obesity Medicine Association (OMA) has stressed the importance of a collaborative approach involving connections with mental health professionals specializing in eating disorders and dietitians.

“If you have a chance to send them to an obesity medicine specialist, you should do that,” said Dr. Cuda, who coauthored the OMA statement. “It’s impractical to expect a primary care physician to do everything: Screen for dietary disorders, do a full dietary counseling, follow up on their activity.”

For patients showing signs of disordered eating, clinicians should avoid recommending restrictive dietary approaches, like cutting out food groups such as carbohydrates or a restricted calorie goal. Instead, they can suggest focusing on healthier lifestyle habits and referring to a psychotherapist, the experts said. Clinicians also should be prepared to adjust or pause GLP-1 agonists if disordered eating disorder symptoms worsen.

“I think a weight-agnostic approach where the focus of care is not weight loss but increase in health protective behaviors and nutritional intake is safest for all kids, especially those with eating disorders or eating disorder risk factors,” Dr. Dennis said.

Various authors of the eating disorder study reported receiving grants, advisory board fees, and speaker fees from entities including the National Health and Medical Research Council of Australia, Eli Lilly, Novo Nordisk, Nu-Mega Ingredients, and the National Institutes of Health, among others.
 

A version of this article appeared on Medscape.com.

As a psychiatrist specializing in eating disorders, Kim Dennis, MD, has seen firsthand the complex relationship between obesity treatment and mental health in adolescents.

Now, with the rising popularity of medications like Ozempic for weight loss, she fears she will care for more teens with eating disorders who are seeking glucagon-like peptide 1 (GLP-1) agonists or who have developed a disorder while taking them.

“We haven’t seen patients yet, but I’m sure they are on their way,” said Dr. Dennis, a clinical assistant professor in the Department of Psychiatry at the University of Illinois College of Medicine in Chicago. She is also the cofounder and chief medical officer of SunCloud Health, an outpatient eating disorder treatment center in Illinois.

Dr. Dennis’ concerns reflect a growing unease among eating disorder specialists as obesity medications gain traction for adolescent use. A recent study published in JAMA Pediatrics showed nearly 80% of teens in treatment for obesity reported symptoms of disordered eating at the outset of an intervention. These included signs of binge eating and loss of control.

The randomized clinical trial, conducted from 2018 to 2023, examined 141 adolescents with obesity undergoing interventions like low-energy diets or intermittent energy restriction. Almost half scored as having risk for an undiagnosed eating disorder, as defined by the Eating Disorder Examination Questionnaire (EDE-Q).

At the end of the intervention, many teens continued to have symptoms of disordered eating, while a smaller group was newly scored as having a risk for an eating disorder.
 

Weight Loss and Eating Disorders: A Balancing Act

The findings illuminate a significant challenge for pediatricians and primary care clinicians: Balancing effective weight management with the risk of exacerbating or triggering eating disorders, said Hiba Jebeile, PhD, a research dietitian at The Children’s Hospital at Westmead in Australia, and the study’s lead author. Adding weight loss medication on top of the equation can further complicate care.

“It is helpful for obesity and eating disorder services to work together, with clear referral pathways, to manage these adolescents,” Dr. Jebeile said.

The US Food and Drug Administration approved semaglutide for weight loss in adolescents aged 12-17 years in December 2020. One study found that the number of adolescents prescribed GLP-1 receptor agonists (GLP-1 RAs) for type 2 diabetes and weight management rose from 8722 to 60,567 between 2020 and 2023 — a nearly sevenfold increase.

“The number of adolescents taking these medications is going up because they work,” said Suzanne Cuda, MD, medical director of Alamo City Healthy Kids and Families, a medical weight management clinic in San Antonio. The medications have been shown to treat type 2 diabetes, lower blood pressure, and reduce the risk for cardiovascular diseases.

“The younger you are, the better the outcome,” Dr. Cuda said.

How GLP-1 agonists may affect adolescents in the long run is not yet clear. Existing studies on GLP-1 medications in patients with eating disorders have shown mixed results. Some studies indicate that the drugs decrease binge episodes for those with binge eating disorder or bulimia nervosa. However, these studies had small sample sizes and measured only short-term effects, leaving long-term outcomes and risks unknown.

Traditional treatments for eating disorders emphasize regular eating patterns, body acceptance, addressing weight stigma, and improving attunement to hunger and fullness cues — approaches that may conflict with the effects of GLP-1 agonists. These drugs suppress appetite, alter metabolic signals, and may unintentionally reinforce weight loss as a primary goal, creating a potential disconnect between the aims of recovery from eating disorders and the biologic effects of the medication, experts said.

Dr. Cuda said she has cared for adolescents with diagnosed eating disorders in her practice who are seeking GLP-1 agonists. She said she first works with patients to treat the underlying disorder before prescribing medication.

“One of the concerns is the extreme reductions in calories that could be induced by GLP-1 RA in children and adolescents,” she said. Unlike adults, adolescents use caloric energy not just for physical activity but also for growing and developing, she said.

“They can’t catch up on that growth and development,” she added.
 

Advice for Screening and Monitoring

The National Eating Disorders Association raised concerns about the potential misuse of these medications and their potential to exacerbate eating disorder behaviors in people who are already at a higher risk of developing one of the conditions, including those with existing mental health disorders, stress, who have already dieted, and who have experienced weight-centric bullying.

Clinicians should be on the lookout for patients seeking GLP-1s who present with symptoms of an eating disorder that may be less apparent, such as picky eating, insomnia or difficulty sleeping, or, for girls, irregular menstrual periods, Dr. Dennis said. These patients may be more likely to go undiagnosed or misdiagnosed. Research also suggests that people of color are less likely to be diagnosed or receive specialty care for eating disorders.

Discussions between patients and clinicians about obesity treatment prior to prescribing provide a crucial opportunity to screen and monitor for disordered eating, which Dr. Dennis said does not universally occur currently.

Dr. Dennis recommended initial assessments using validated screening tools like the EDE-Q and the Center for Epidemiologic Studies Depression Scale Revised, 10-Item Version.

Ongoing monitoring throughout treatment is essential, with initial monthly check-ins that include dietary counseling to detect subtle changes in eating behaviors or attitudes toward food and body image, Dr. Cuda said.

The Obesity Medicine Association (OMA) has stressed the importance of a collaborative approach involving connections with mental health professionals specializing in eating disorders and dietitians.

“If you have a chance to send them to an obesity medicine specialist, you should do that,” said Dr. Cuda, who coauthored the OMA statement. “It’s impractical to expect a primary care physician to do everything: Screen for dietary disorders, do a full dietary counseling, follow up on their activity.”

For patients showing signs of disordered eating, clinicians should avoid recommending restrictive dietary approaches, like cutting out food groups such as carbohydrates or a restricted calorie goal. Instead, they can suggest focusing on healthier lifestyle habits and referring to a psychotherapist, the experts said. Clinicians also should be prepared to adjust or pause GLP-1 agonists if disordered eating disorder symptoms worsen.

“I think a weight-agnostic approach where the focus of care is not weight loss but increase in health protective behaviors and nutritional intake is safest for all kids, especially those with eating disorders or eating disorder risk factors,” Dr. Dennis said.

Various authors of the eating disorder study reported receiving grants, advisory board fees, and speaker fees from entities including the National Health and Medical Research Council of Australia, Eli Lilly, Novo Nordisk, Nu-Mega Ingredients, and the National Institutes of Health, among others.
 

A version of this article appeared on Medscape.com.

As a psychiatrist specializing in eating disorders, Kim Dennis, MD, has seen firsthand the complex relationship between obesity treatment and mental health in adolescents.

Now, with the rising popularity of medications like Ozempic for weight loss, she fears she will care for more teens with eating disorders who are seeking glucagon-like peptide 1 (GLP-1) agonists or who have developed a disorder while taking them.

“We haven’t seen patients yet, but I’m sure they are on their way,” said Dr. Dennis, a clinical assistant professor in the Department of Psychiatry at the University of Illinois College of Medicine in Chicago. She is also the cofounder and chief medical officer of SunCloud Health, an outpatient eating disorder treatment center in Illinois.

Dr. Dennis’ concerns reflect a growing unease among eating disorder specialists as obesity medications gain traction for adolescent use. A recent study published in JAMA Pediatrics showed nearly 80% of teens in treatment for obesity reported symptoms of disordered eating at the outset of an intervention. These included signs of binge eating and loss of control.

The randomized clinical trial, conducted from 2018 to 2023, examined 141 adolescents with obesity undergoing interventions like low-energy diets or intermittent energy restriction. Almost half scored as having risk for an undiagnosed eating disorder, as defined by the Eating Disorder Examination Questionnaire (EDE-Q).

At the end of the intervention, many teens continued to have symptoms of disordered eating, while a smaller group was newly scored as having a risk for an eating disorder.
 

Weight Loss and Eating Disorders: A Balancing Act

The findings illuminate a significant challenge for pediatricians and primary care clinicians: Balancing effective weight management with the risk of exacerbating or triggering eating disorders, said Hiba Jebeile, PhD, a research dietitian at The Children’s Hospital at Westmead in Australia, and the study’s lead author. Adding weight loss medication on top of the equation can further complicate care.

“It is helpful for obesity and eating disorder services to work together, with clear referral pathways, to manage these adolescents,” Dr. Jebeile said.

The US Food and Drug Administration approved semaglutide for weight loss in adolescents aged 12-17 years in December 2020. One study found that the number of adolescents prescribed GLP-1 receptor agonists (GLP-1 RAs) for type 2 diabetes and weight management rose from 8722 to 60,567 between 2020 and 2023 — a nearly sevenfold increase.

“The number of adolescents taking these medications is going up because they work,” said Suzanne Cuda, MD, medical director of Alamo City Healthy Kids and Families, a medical weight management clinic in San Antonio. The medications have been shown to treat type 2 diabetes, lower blood pressure, and reduce the risk for cardiovascular diseases.

“The younger you are, the better the outcome,” Dr. Cuda said.

How GLP-1 agonists may affect adolescents in the long run is not yet clear. Existing studies on GLP-1 medications in patients with eating disorders have shown mixed results. Some studies indicate that the drugs decrease binge episodes for those with binge eating disorder or bulimia nervosa. However, these studies had small sample sizes and measured only short-term effects, leaving long-term outcomes and risks unknown.

Traditional treatments for eating disorders emphasize regular eating patterns, body acceptance, addressing weight stigma, and improving attunement to hunger and fullness cues — approaches that may conflict with the effects of GLP-1 agonists. These drugs suppress appetite, alter metabolic signals, and may unintentionally reinforce weight loss as a primary goal, creating a potential disconnect between the aims of recovery from eating disorders and the biologic effects of the medication, experts said.

Dr. Cuda said she has cared for adolescents with diagnosed eating disorders in her practice who are seeking GLP-1 agonists. She said she first works with patients to treat the underlying disorder before prescribing medication.

“One of the concerns is the extreme reductions in calories that could be induced by GLP-1 RA in children and adolescents,” she said. Unlike adults, adolescents use caloric energy not just for physical activity but also for growing and developing, she said.

“They can’t catch up on that growth and development,” she added.
 

Advice for Screening and Monitoring

The National Eating Disorders Association raised concerns about the potential misuse of these medications and their potential to exacerbate eating disorder behaviors in people who are already at a higher risk of developing one of the conditions, including those with existing mental health disorders, stress, who have already dieted, and who have experienced weight-centric bullying.

Clinicians should be on the lookout for patients seeking GLP-1s who present with symptoms of an eating disorder that may be less apparent, such as picky eating, insomnia or difficulty sleeping, or, for girls, irregular menstrual periods, Dr. Dennis said. These patients may be more likely to go undiagnosed or misdiagnosed. Research also suggests that people of color are less likely to be diagnosed or receive specialty care for eating disorders.

Discussions between patients and clinicians about obesity treatment prior to prescribing provide a crucial opportunity to screen and monitor for disordered eating, which Dr. Dennis said does not universally occur currently.

Dr. Dennis recommended initial assessments using validated screening tools like the EDE-Q and the Center for Epidemiologic Studies Depression Scale Revised, 10-Item Version.

Ongoing monitoring throughout treatment is essential, with initial monthly check-ins that include dietary counseling to detect subtle changes in eating behaviors or attitudes toward food and body image, Dr. Cuda said.

The Obesity Medicine Association (OMA) has stressed the importance of a collaborative approach involving connections with mental health professionals specializing in eating disorders and dietitians.

“If you have a chance to send them to an obesity medicine specialist, you should do that,” said Dr. Cuda, who coauthored the OMA statement. “It’s impractical to expect a primary care physician to do everything: Screen for dietary disorders, do a full dietary counseling, follow up on their activity.”

For patients showing signs of disordered eating, clinicians should avoid recommending restrictive dietary approaches, like cutting out food groups such as carbohydrates or a restricted calorie goal. Instead, they can suggest focusing on healthier lifestyle habits and referring to a psychotherapist, the experts said. Clinicians also should be prepared to adjust or pause GLP-1 agonists if disordered eating disorder symptoms worsen.

“I think a weight-agnostic approach where the focus of care is not weight loss but increase in health protective behaviors and nutritional intake is safest for all kids, especially those with eating disorders or eating disorder risk factors,” Dr. Dennis said.

Various authors of the eating disorder study reported receiving grants, advisory board fees, and speaker fees from entities including the National Health and Medical Research Council of Australia, Eli Lilly, Novo Nordisk, Nu-Mega Ingredients, and the National Institutes of Health, among others.
 

A version of this article appeared on Medscape.com.

In a review of 32 mixed-type human studies, multinational researchers found a growing association between various classes of environmental pollutants and the risk for inflammatory bowel disease (IBD).

The culprit environmental substances include heavy and transition metals, air pollutants, pesticides, and industrial contaminants. The latter encompass synthetic chemicals such as perfluoroalkyls and polyfluoroalkyls (PFAs), which are present in many common household products.

In contrast, zinc exposure may have a protective, anti-inflammatory effect, according to a research group led by Maria Manuela Estevinho, MD, of the Department of Gastroenterology of the Unidade Local de Saúde Gaia e Espinho in Vila Nova de Gaia, Portugal.

Published in Gut , the review also found limited data suggesting adverse IBD outcomes such as hospitalizations are more prevalent with increased exposure to air contaminants in particular.

“These data carry relevance toward counseling patients and family members,” coauthor Manasi Agrawal, MD, assistant professor of medicine at the Icahn School of Medicine, Mount Sinai, and a gastroenterologist at Mount Sinai Hospital in New York City, said in an interview. “At the individual level, we can try to decrease our exposure to chemicals; for example, to minimize use of pesticides and products containing in our homes. However, at the broader community level, health policy changes are needed to help with mitigation strategies and curb production.”

Icahn School of Medicine at Mount Sinai

• Heavy and transition metals such as copper, lead, and cadmium were associated with gut dysbiosis, overgrowth of undesirable species of microorganisms, and loss of tight junction proteins leading to leaky gut. In all studies, individuals with IBD showed higher concentrations of such metals than healthy control individuals. While the specific profile of heavy metals varied across studies, lead, copper, and iron, were linked to IBD risk in more than one study.
• The particulate matter present in air pollution — including agricultural and wood dust as well as volcanic ash and hydrocarbon dioxin — was linked to dysbiosis and tight junction protein loss. Air pollution has also been linked to increased incidence of irritable bowel syndrome.
• Industrial and organic pollutants such as perfluoroalkyl and polyfluoroalkyl compounds, triclocarban, and polychlorinated biphenyls were also associated with gut permeability and/or reduced microbial diversity.
• Pesticides such as PFAs, organochloride and organophosphate compounds, and pyrethroids were associated with loss of tight junction proteins.
• Zinc was linked to an increase in tight junction proteins.

Commenting on the review but not involved in it, Ashwin N. Ananthakrishnan, MBBS, MD, MPH, AGAF, director of the Crohn’s and Colitis Center at Massachusetts General Hospital, and associate professor at Harvard Medical School in Boston, called it a very important study that expands our understanding of the role of environment in IBD.

A version of this article appeared on Medscape.com.

In a review of 32 mixed-type human studies, multinational researchers found a growing association between various classes of environmental pollutants and the risk for inflammatory bowel disease (IBD).

The culprit environmental substances include heavy and transition metals, air pollutants, pesticides, and industrial contaminants. The latter encompass synthetic chemicals such as perfluoroalkyls and polyfluoroalkyls (PFAs), which are present in many common household products.

In contrast, zinc exposure may have a protective, anti-inflammatory effect, according to a research group led by Maria Manuela Estevinho, MD, of the Department of Gastroenterology of the Unidade Local de Saúde Gaia e Espinho in Vila Nova de Gaia, Portugal.

Published in Gut , the review also found limited data suggesting adverse IBD outcomes such as hospitalizations are more prevalent with increased exposure to air contaminants in particular.

“These data carry relevance toward counseling patients and family members,” coauthor Manasi Agrawal, MD, assistant professor of medicine at the Icahn School of Medicine, Mount Sinai, and a gastroenterologist at Mount Sinai Hospital in New York City, said in an interview. “At the individual level, we can try to decrease our exposure to chemicals; for example, to minimize use of pesticides and products containing in our homes. However, at the broader community level, health policy changes are needed to help with mitigation strategies and curb production.”

Icahn School of Medicine at Mount Sinai

• Heavy and transition metals such as copper, lead, and cadmium were associated with gut dysbiosis, overgrowth of undesirable species of microorganisms, and loss of tight junction proteins leading to leaky gut. In all studies, individuals with IBD showed higher concentrations of such metals than healthy control individuals. While the specific profile of heavy metals varied across studies, lead, copper, and iron, were linked to IBD risk in more than one study.
• The particulate matter present in air pollution — including agricultural and wood dust as well as volcanic ash and hydrocarbon dioxin — was linked to dysbiosis and tight junction protein loss. Air pollution has also been linked to increased incidence of irritable bowel syndrome.
• Industrial and organic pollutants such as perfluoroalkyl and polyfluoroalkyl compounds, triclocarban, and polychlorinated biphenyls were also associated with gut permeability and/or reduced microbial diversity.
• Pesticides such as PFAs, organochloride and organophosphate compounds, and pyrethroids were associated with loss of tight junction proteins.
• Zinc was linked to an increase in tight junction proteins.

Commenting on the review but not involved in it, Ashwin N. Ananthakrishnan, MBBS, MD, MPH, AGAF, director of the Crohn’s and Colitis Center at Massachusetts General Hospital, and associate professor at Harvard Medical School in Boston, called it a very important study that expands our understanding of the role of environment in IBD.

A version of this article appeared on Medscape.com.

In a review of 32 mixed-type human studies, multinational researchers found a growing association between various classes of environmental pollutants and the risk for inflammatory bowel disease (IBD).

The culprit environmental substances include heavy and transition metals, air pollutants, pesticides, and industrial contaminants. The latter encompass synthetic chemicals such as perfluoroalkyls and polyfluoroalkyls (PFAs), which are present in many common household products.

In contrast, zinc exposure may have a protective, anti-inflammatory effect, according to a research group led by Maria Manuela Estevinho, MD, of the Department of Gastroenterology of the Unidade Local de Saúde Gaia e Espinho in Vila Nova de Gaia, Portugal.

Published in Gut , the review also found limited data suggesting adverse IBD outcomes such as hospitalizations are more prevalent with increased exposure to air contaminants in particular.

“These data carry relevance toward counseling patients and family members,” coauthor Manasi Agrawal, MD, assistant professor of medicine at the Icahn School of Medicine, Mount Sinai, and a gastroenterologist at Mount Sinai Hospital in New York City, said in an interview. “At the individual level, we can try to decrease our exposure to chemicals; for example, to minimize use of pesticides and products containing in our homes. However, at the broader community level, health policy changes are needed to help with mitigation strategies and curb production.”

Icahn School of Medicine at Mount Sinai

• Heavy and transition metals such as copper, lead, and cadmium were associated with gut dysbiosis, overgrowth of undesirable species of microorganisms, and loss of tight junction proteins leading to leaky gut. In all studies, individuals with IBD showed higher concentrations of such metals than healthy control individuals. While the specific profile of heavy metals varied across studies, lead, copper, and iron, were linked to IBD risk in more than one study.
• The particulate matter present in air pollution — including agricultural and wood dust as well as volcanic ash and hydrocarbon dioxin — was linked to dysbiosis and tight junction protein loss. Air pollution has also been linked to increased incidence of irritable bowel syndrome.
• Industrial and organic pollutants such as perfluoroalkyl and polyfluoroalkyl compounds, triclocarban, and polychlorinated biphenyls were also associated with gut permeability and/or reduced microbial diversity.
• Pesticides such as PFAs, organochloride and organophosphate compounds, and pyrethroids were associated with loss of tight junction proteins.
• Zinc was linked to an increase in tight junction proteins.

Commenting on the review but not involved in it, Ashwin N. Ananthakrishnan, MBBS, MD, MPH, AGAF, director of the Crohn’s and Colitis Center at Massachusetts General Hospital, and associate professor at Harvard Medical School in Boston, called it a very important study that expands our understanding of the role of environment in IBD.

A version of this article appeared on Medscape.com.

COPENHAGEN — Relative to starting on an immunomodulator and then switching to a more potent anti-CD20 monoclonal antibody, the likelihood of long-term accumulation of disability in patients with multiple sclerosis (MS) is significantly lower if the more potent drug is started first, according to extension data out to 6 years.

By the most recent analysis of a phase 3 extension study, there were “fewer disability worsening events and greater likelihood of being progression free among those started on ofatumumab than those started on teriflunomide and switched,” reported Amit Bar-Or, MD, director of the Center of Neuroinflammation and Neurotherapeutics, University of Pennsylvania, Philadelphia.

Stated differently, if ofatumumab is delayed, it never fully compensates for the advantage of better early MS control in treatment-naïve patients, according to Dr. Bar-Or, who presented these data at the 2024 ECTRIMS annual meeting.
 

Anti-CD20 Disability Protection Already Seen in Pivotal Trial

In two phase 3 trials called ASCLEPIOS I and II that were published together several years ago in The New England Journal of Medicine, the anti-CD20 monoclonal antibody ofatumumab reduced the annualized relapse rate (ARR) by half (0.11 vs. 0.22). While ARR was the primary endpoint, ofatumumab was also associated with a 34% reduction (P = .002) in risk of confirmed disability worsening at 3 months (3mCDW) at a medium follow-up of 1.6 years.

After the completion of ASCLEPIOS I and II, the majority of both arms of the study were enrolled in the ALITHIOS extension study. Patients in ofatumumab arm have remained on their initially assigned drug. Patients in the teriflunomide group were switched. Characterized as the delayed ofatumumab group, they have been receiving the same 20-mg, once-monthly subcutaneous (SQ) dose of ofatumumab as those initially assigned to this drug. ALITHIOS will continue to follow both groups until 2028.

Patients have now been followed for up to 6 years. In the latest results presented at ECTRIMS, data were available for 690 patients on continuous treatment and 677 switch patients. Baseline characteristics of the two groups were similar. About half of each group were treatment naive when enrolled in the ASCLEPIOS trials.

Whether compared for 6-month confirmed disability worsening (6mCDW), 6-month progression independent of relapse activity (6mPIRA) or 6-month relapse-associated worsening (6mRAW), disease progression was consistently worse for those with delayed ofatumumab. The differences were most pronounced in those who were treatment naive when started on therapy.
 

Anti-CD20 MAB sustains Disability Protection for up to Years

For those who were treatment naive, the rates of 6mCDW at the most recent follow-up were 16.61% vs 23.74% (P = .033) for continuous and delayed ofatumumab, respectively. For the entire study, these rates were 21.09% versus 24.77%, respectively, which represented a strong trend (P = .063).

The relative rates for 6mPIRA (11.12% vs 16.75%) and 6mRAW (4.26% vs 4.82%) in treatment-naive patients also favored continuous over delayed ofatumumab, and the numerical advantage was also seen with up to 6 years of follow-up in the overall study population for 6mPIRA (15.45% vs 16.56%) and 6mRAW (5.24% vs 5.81%).

Translating these into freedom from disability, Dr. Bar-Or reported that more than 80% (83.4%) of patients on continuous ofatumumab were progression free for up to 6 years, a figure that exceeded the 76.3% free of progression in the delayed ofatumumab group.

On the basis of 6mPIRA, that absence of disability progression neared 90% (88.9%) on continuous ofatumumab relative to 83.3% for delayed ofatumumab.

An advantage for a reduction in disability accumulation for ofatumumab relative to teriflunomide was established at the end of the ASCLEPIOS I and II trial, but the latest follow-up shows that it is “sustained out to 6 years.” The advantage is achieved with no greater cost in adverse events during the early treatment period, according to Dr. Bar-Or, who noted that ofatumumab and teriflunomide were similarly well tolerated in ASCLEPIOS I and II.
 

No New Gd T1 Lesions Observed Over 12 Months

Although other anti-CD20 monoclonal antibodies have also been shown to be highly effective and often more effective than immunomodulators in the first- and second-line treatment of relapsing remitting MS (RRMS), another set of data presented at ECTRIMS 2024 looked specifically at transitioning from intravenous (IV) anti-CD20 drugs to SQ ofatumumab.

In this study, called OLIKOS, 102 RRMS patients who had received either IV ocrelizumab or IV rituximab were followed after transitioning to ofatumumab administered SQ with an autoinjector pen. The primary endpoint was the proportion of patients with no change or a reduction gadolinium-enhancing (Gd) T1 lesions over 12 months of follow-up.

“At month 12, 84 of 84 evaluable patients with evaluable MRI assessments met the primary endpoint,” reported the principal investigator Le Hua, MD, director of the Multiple Sclerosis Program, Cleveland Clinic in Ohio.

At 12 months, there were also no new or enlarging T2 lesions in 98% of patients receiving SQ ofatumumab following the transition from one of the other anti-CD20 IV drugs, but Dr. Hua characterized this as an exploratory endpoint.

The safety and tolerability data during the OLIKOS study was also reassuring with no new or unexpected safety signals for SQ ofatumumab, which has been well tolerated in the phase 3 development program. IgM and IgG levels remained stable over the course of follow-up.

High-efficacy anti-CD20 drugs were once reserved for RRMS patients with highly active disease, but long-term data, such as those generated by the ALITHIOS extension study, suggest greater efficacy with acceptable safety of these agents relative to conventional first-line RRMS therapies. Based on ALITHIOS data, Dr. Bar-Or suggested that early use of the most effective therapy appears to lead to better long-term protection from increased cumulative disability.

Dr. Bar-Or reported financial relationships with Accure, Atara, Biogen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Gossamer, Janssen/Actelion, Medimmune, Merck/EMD Serono, Novartis, Roche/Genentech, and Sanofi-Genzyme. Dr. Hua reported financial relationships with Alexion, EMD Serono, Genentech, Horizon, Novartis, and TG Therapeutics.

COPENHAGEN — Relative to starting on an immunomodulator and then switching to a more potent anti-CD20 monoclonal antibody, the likelihood of long-term accumulation of disability in patients with multiple sclerosis (MS) is significantly lower if the more potent drug is started first, according to extension data out to 6 years.

By the most recent analysis of a phase 3 extension study, there were “fewer disability worsening events and greater likelihood of being progression free among those started on ofatumumab than those started on teriflunomide and switched,” reported Amit Bar-Or, MD, director of the Center of Neuroinflammation and Neurotherapeutics, University of Pennsylvania, Philadelphia.

Stated differently, if ofatumumab is delayed, it never fully compensates for the advantage of better early MS control in treatment-naïve patients, according to Dr. Bar-Or, who presented these data at the 2024 ECTRIMS annual meeting.
 

Anti-CD20 Disability Protection Already Seen in Pivotal Trial

In two phase 3 trials called ASCLEPIOS I and II that were published together several years ago in The New England Journal of Medicine, the anti-CD20 monoclonal antibody ofatumumab reduced the annualized relapse rate (ARR) by half (0.11 vs. 0.22). While ARR was the primary endpoint, ofatumumab was also associated with a 34% reduction (P = .002) in risk of confirmed disability worsening at 3 months (3mCDW) at a medium follow-up of 1.6 years.

After the completion of ASCLEPIOS I and II, the majority of both arms of the study were enrolled in the ALITHIOS extension study. Patients in ofatumumab arm have remained on their initially assigned drug. Patients in the teriflunomide group were switched. Characterized as the delayed ofatumumab group, they have been receiving the same 20-mg, once-monthly subcutaneous (SQ) dose of ofatumumab as those initially assigned to this drug. ALITHIOS will continue to follow both groups until 2028.

Patients have now been followed for up to 6 years. In the latest results presented at ECTRIMS, data were available for 690 patients on continuous treatment and 677 switch patients. Baseline characteristics of the two groups were similar. About half of each group were treatment naive when enrolled in the ASCLEPIOS trials.

Whether compared for 6-month confirmed disability worsening (6mCDW), 6-month progression independent of relapse activity (6mPIRA) or 6-month relapse-associated worsening (6mRAW), disease progression was consistently worse for those with delayed ofatumumab. The differences were most pronounced in those who were treatment naive when started on therapy.
 

Anti-CD20 MAB sustains Disability Protection for up to Years

For those who were treatment naive, the rates of 6mCDW at the most recent follow-up were 16.61% vs 23.74% (P = .033) for continuous and delayed ofatumumab, respectively. For the entire study, these rates were 21.09% versus 24.77%, respectively, which represented a strong trend (P = .063).

The relative rates for 6mPIRA (11.12% vs 16.75%) and 6mRAW (4.26% vs 4.82%) in treatment-naive patients also favored continuous over delayed ofatumumab, and the numerical advantage was also seen with up to 6 years of follow-up in the overall study population for 6mPIRA (15.45% vs 16.56%) and 6mRAW (5.24% vs 5.81%).

Translating these into freedom from disability, Dr. Bar-Or reported that more than 80% (83.4%) of patients on continuous ofatumumab were progression free for up to 6 years, a figure that exceeded the 76.3% free of progression in the delayed ofatumumab group.

On the basis of 6mPIRA, that absence of disability progression neared 90% (88.9%) on continuous ofatumumab relative to 83.3% for delayed ofatumumab.

An advantage for a reduction in disability accumulation for ofatumumab relative to teriflunomide was established at the end of the ASCLEPIOS I and II trial, but the latest follow-up shows that it is “sustained out to 6 years.” The advantage is achieved with no greater cost in adverse events during the early treatment period, according to Dr. Bar-Or, who noted that ofatumumab and teriflunomide were similarly well tolerated in ASCLEPIOS I and II.
 

No New Gd T1 Lesions Observed Over 12 Months

Although other anti-CD20 monoclonal antibodies have also been shown to be highly effective and often more effective than immunomodulators in the first- and second-line treatment of relapsing remitting MS (RRMS), another set of data presented at ECTRIMS 2024 looked specifically at transitioning from intravenous (IV) anti-CD20 drugs to SQ ofatumumab.

In this study, called OLIKOS, 102 RRMS patients who had received either IV ocrelizumab or IV rituximab were followed after transitioning to ofatumumab administered SQ with an autoinjector pen. The primary endpoint was the proportion of patients with no change or a reduction gadolinium-enhancing (Gd) T1 lesions over 12 months of follow-up.

“At month 12, 84 of 84 evaluable patients with evaluable MRI assessments met the primary endpoint,” reported the principal investigator Le Hua, MD, director of the Multiple Sclerosis Program, Cleveland Clinic in Ohio.

At 12 months, there were also no new or enlarging T2 lesions in 98% of patients receiving SQ ofatumumab following the transition from one of the other anti-CD20 IV drugs, but Dr. Hua characterized this as an exploratory endpoint.

The safety and tolerability data during the OLIKOS study was also reassuring with no new or unexpected safety signals for SQ ofatumumab, which has been well tolerated in the phase 3 development program. IgM and IgG levels remained stable over the course of follow-up.

High-efficacy anti-CD20 drugs were once reserved for RRMS patients with highly active disease, but long-term data, such as those generated by the ALITHIOS extension study, suggest greater efficacy with acceptable safety of these agents relative to conventional first-line RRMS therapies. Based on ALITHIOS data, Dr. Bar-Or suggested that early use of the most effective therapy appears to lead to better long-term protection from increased cumulative disability.

Dr. Bar-Or reported financial relationships with Accure, Atara, Biogen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Gossamer, Janssen/Actelion, Medimmune, Merck/EMD Serono, Novartis, Roche/Genentech, and Sanofi-Genzyme. Dr. Hua reported financial relationships with Alexion, EMD Serono, Genentech, Horizon, Novartis, and TG Therapeutics.

COPENHAGEN — Relative to starting on an immunomodulator and then switching to a more potent anti-CD20 monoclonal antibody, the likelihood of long-term accumulation of disability in patients with multiple sclerosis (MS) is significantly lower if the more potent drug is started first, according to extension data out to 6 years.

By the most recent analysis of a phase 3 extension study, there were “fewer disability worsening events and greater likelihood of being progression free among those started on ofatumumab than those started on teriflunomide and switched,” reported Amit Bar-Or, MD, director of the Center of Neuroinflammation and Neurotherapeutics, University of Pennsylvania, Philadelphia.

Stated differently, if ofatumumab is delayed, it never fully compensates for the advantage of better early MS control in treatment-naïve patients, according to Dr. Bar-Or, who presented these data at the 2024 ECTRIMS annual meeting.
 

Anti-CD20 Disability Protection Already Seen in Pivotal Trial

In two phase 3 trials called ASCLEPIOS I and II that were published together several years ago in The New England Journal of Medicine, the anti-CD20 monoclonal antibody ofatumumab reduced the annualized relapse rate (ARR) by half (0.11 vs. 0.22). While ARR was the primary endpoint, ofatumumab was also associated with a 34% reduction (P = .002) in risk of confirmed disability worsening at 3 months (3mCDW) at a medium follow-up of 1.6 years.

After the completion of ASCLEPIOS I and II, the majority of both arms of the study were enrolled in the ALITHIOS extension study. Patients in ofatumumab arm have remained on their initially assigned drug. Patients in the teriflunomide group were switched. Characterized as the delayed ofatumumab group, they have been receiving the same 20-mg, once-monthly subcutaneous (SQ) dose of ofatumumab as those initially assigned to this drug. ALITHIOS will continue to follow both groups until 2028.

Patients have now been followed for up to 6 years. In the latest results presented at ECTRIMS, data were available for 690 patients on continuous treatment and 677 switch patients. Baseline characteristics of the two groups were similar. About half of each group were treatment naive when enrolled in the ASCLEPIOS trials.

Whether compared for 6-month confirmed disability worsening (6mCDW), 6-month progression independent of relapse activity (6mPIRA) or 6-month relapse-associated worsening (6mRAW), disease progression was consistently worse for those with delayed ofatumumab. The differences were most pronounced in those who were treatment naive when started on therapy.
 

Anti-CD20 MAB sustains Disability Protection for up to Years

For those who were treatment naive, the rates of 6mCDW at the most recent follow-up were 16.61% vs 23.74% (P = .033) for continuous and delayed ofatumumab, respectively. For the entire study, these rates were 21.09% versus 24.77%, respectively, which represented a strong trend (P = .063).

The relative rates for 6mPIRA (11.12% vs 16.75%) and 6mRAW (4.26% vs 4.82%) in treatment-naive patients also favored continuous over delayed ofatumumab, and the numerical advantage was also seen with up to 6 years of follow-up in the overall study population for 6mPIRA (15.45% vs 16.56%) and 6mRAW (5.24% vs 5.81%).

Translating these into freedom from disability, Dr. Bar-Or reported that more than 80% (83.4%) of patients on continuous ofatumumab were progression free for up to 6 years, a figure that exceeded the 76.3% free of progression in the delayed ofatumumab group.

On the basis of 6mPIRA, that absence of disability progression neared 90% (88.9%) on continuous ofatumumab relative to 83.3% for delayed ofatumumab.

An advantage for a reduction in disability accumulation for ofatumumab relative to teriflunomide was established at the end of the ASCLEPIOS I and II trial, but the latest follow-up shows that it is “sustained out to 6 years.” The advantage is achieved with no greater cost in adverse events during the early treatment period, according to Dr. Bar-Or, who noted that ofatumumab and teriflunomide were similarly well tolerated in ASCLEPIOS I and II.
 

No New Gd T1 Lesions Observed Over 12 Months

Although other anti-CD20 monoclonal antibodies have also been shown to be highly effective and often more effective than immunomodulators in the first- and second-line treatment of relapsing remitting MS (RRMS), another set of data presented at ECTRIMS 2024 looked specifically at transitioning from intravenous (IV) anti-CD20 drugs to SQ ofatumumab.

In this study, called OLIKOS, 102 RRMS patients who had received either IV ocrelizumab or IV rituximab were followed after transitioning to ofatumumab administered SQ with an autoinjector pen. The primary endpoint was the proportion of patients with no change or a reduction gadolinium-enhancing (Gd) T1 lesions over 12 months of follow-up.

“At month 12, 84 of 84 evaluable patients with evaluable MRI assessments met the primary endpoint,” reported the principal investigator Le Hua, MD, director of the Multiple Sclerosis Program, Cleveland Clinic in Ohio.

At 12 months, there were also no new or enlarging T2 lesions in 98% of patients receiving SQ ofatumumab following the transition from one of the other anti-CD20 IV drugs, but Dr. Hua characterized this as an exploratory endpoint.

The safety and tolerability data during the OLIKOS study was also reassuring with no new or unexpected safety signals for SQ ofatumumab, which has been well tolerated in the phase 3 development program. IgM and IgG levels remained stable over the course of follow-up.

High-efficacy anti-CD20 drugs were once reserved for RRMS patients with highly active disease, but long-term data, such as those generated by the ALITHIOS extension study, suggest greater efficacy with acceptable safety of these agents relative to conventional first-line RRMS therapies. Based on ALITHIOS data, Dr. Bar-Or suggested that early use of the most effective therapy appears to lead to better long-term protection from increased cumulative disability.

Dr. Bar-Or reported financial relationships with Accure, Atara, Biogen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Gossamer, Janssen/Actelion, Medimmune, Merck/EMD Serono, Novartis, Roche/Genentech, and Sanofi-Genzyme. Dr. Hua reported financial relationships with Alexion, EMD Serono, Genentech, Horizon, Novartis, and TG Therapeutics.

The Food and Drug Administration (FDA) plans to scrutinize the safety and efficacy of lab-developed tests — those designed, manufactured, and used in a single laboratory — far more thoroughly in the future.

Under a rule finalized in April, the FDA will treat facilities that develop and use lab tests as manufacturers and regulate tests as medical devices. That means that most lab tests will need an FDA review before going on sale.

The FDA will also impose new quality standards, requiring test manufacturers to report adverse events and create a registry of lab tests under the new rule, which will be phased in over 4 years.

FDA officials have been concerned for years about the reliability of commercial lab tests, which have ballooned into a multibillion-dollar industry.

Consumer groups have long urged the FDA to regulate lab tests more strictly, arguing that the lack of scrutiny allows doctors and patients to be exploited by bad actors such as Theranos, which falsely claimed that its tests could diagnose multiple diseases with a single drop of blood.

“When it comes to some of these tests that doctors are recommending for patients, many doctors are just crossing their fingers and relying on the representation of the company because nobody is checking” to verify a manufacturer’s claims, said Joshua Sharfstein, MD, vice dean for public health practice and community engagement at the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
 

Nearly 12,000 Labs Making Medical Tests

Although the FDA estimates there are nearly 12,000 labs manufacturing medical tests, agency officials said they don’t know how many tests are being marketed. The FDA already requires that home test kits marketed directly to consumers, such as those used to detect COVID-19, get clearance from the agency before being sold.

“There’s plenty of time for industry to get its act together to develop the data that it might need to make a premarket application,” said Peter Lurie, MD, PhD, a former associate commissioner at the FDA. In 2015, Dr. Lurie led a report outlining some of the dangers of unregulated lab tests.

For the average physician who orders lab tests, nothing is going to immediately change because of the final rule, said Dr. Lurie, now president of the Center for Science in the Public Interest, a nonprofit consumer watchdog.

“Tomorrow, this will look just the same as it does today,” Dr. Lurie said. “For the next 3 years, the companies will be scurrying behind the scenes to comply with the early stages of implementation. But most of that will be invisible to the average practitioner.”

Dr. Lurie predicted the FDA will focus its scrutiny on tests that pose the greatest potential risk to patients, such as ones used to diagnose serious diseases or guide treatment for life-threatening conditions. “The least significant tests will likely get very limited, if any, scrutiny,” said Dr. Lurie, adding that the FDA will likely issue guidance about how it plans to define low- and high-risk tests. “My suspicion is that it will be probably a small minority of products that are subject to full premarket approval.”
 

Lab Industry Groups Push Back

But imposing new rules with the potential to affect an industry’s bottom line is no easy task.

The American Clinical Laboratory Association, which represents the lab industry, said in a statement that the FDA rule will “limit access to scores of critical tests, increase healthcare costs, and undermine innovation in new diagnostics.” Another industry group, the Association for Molecular Pathology, has warned of “significant and harmful disruption to laboratory medicine.”

The two associations have filed separate lawsuits, charging that the FDA overstepped the authority granted by Congress. In their lawsuits, groups claim that lab tests are professional services, not manufactured products. The groups noted that the Centers for Medicare & Medicaid Services (CMS) already inspects lab facilities. CMS does not assess the tests’ quality or reliability.

A recent Supreme Court decision could make those lawsuits more likely to succeed, said David Simon, JD, LLM, PhD, an assistant professor of law at the Northeastern University School of Law, Boston, Massachusetts.

In the case of Loper Bright Enterprises v. Raimondo, decided in June, justices overturned a long-standing precedent known as Chevron deference, which required courts to defer to federal agencies when interpreting ambiguous laws. That means that courts no longer have to accept the FDA’s definition of a device, Dr. Simon said.

“Because judges may have more active roles in defining agency authority, federal agencies may have correspondingly less robust roles in policymaking,” Dr. Simon wrote in an editorial coauthored with Michael J. Young, MD, MPhil, of Harvard Medical School, Boston.

The Supreme Court ruling could pressure Congress to more clearly define FDA’s ruling in regulating lab tests, Dr. Simon and Dr. Young wrote.

Members of Congress first introduced a bill to clarify the FDA’s role in regulating lab tests, called the VALID Act, in 2020. The bill stalled and, despite efforts to revive it, still hasn’t passed.

FDA officials have said they remain “open to working with Congress,” noting that any future legislation about lab-developed tests would supersede their current policy.

In an interview, Dr. Simon noted the FDA significantly narrowed the scope of the final rule in response to comments from critics who objected to an earlier version of the policy proposed in 2023. The final rule carves out several categories of tests that won’t need to apply for “premarket review.”

Notably, a “grandfather clause” will allow some lab tests already on the market to continue being sold without undergoing FDA’s premarket review process. In explaining the exemption, FDA officials said they did not want doctors and patients to lose access to tests on which they rely. But Dr. Lurie noted that because the FDA views all these tests as under its jurisdiction, the agency could opt to take a closer look “at a very old device that is causing a problem today.”

The FDA also will exempt tests approved by New York State’s Clinical Laboratory Evaluation Program, which conducts its own stringent reviews. And the FDA will continue to allow hospitals to develop tests for patients within their healthcare system without going through the FDA approval process, if no FDA-approved tests are available.

Hospital-based tests play a critical role in treating infectious diseases, said Amesh Adalja, MD, an infectious diseases specialist and senior scholar at the Johns Hopkins Center for Health Security. For example, a large research hospital treating a patient with cytomegalovirus may need to develop its own test to determine whether the infection is resistant to antiviral drugs, Dr. Adalja said.

“With novel infectious disease outbreaks, researchers are able to move quickly to make diagnostic tests months and months before commercial laboratories are able to get through regulatory processes,” Dr. Adalja said.

To help scientists respond quickly to emergencies, the FDA published special guidance for labs that develop unauthorized lab tests for disease outbreaks.

Medical groups such as the American Hospital Association and Infectious Diseases Society of America remain concerned about the burden of complying with new regulations.

“Many vital tests developed in hospitals and health systems may be subjected to unnecessary and costly paperwork,” said Stacey Hughes, executive vice president of the American Hospital Association, in a statement.

Other groups, such as the American Society of Clinical Oncology, praised the new FDA policy. In comments submitted to the FDA in 2023, the cancer group said it “emphatically supports” requiring lab tests to undergo FDA review.

“We appreciate FDA action to modernize oversight of these tests and are hopeful this rule will increase focus on the need to balance rapid diagnostic innovation with patient safety and access” Everett Vokes, MD, the group’s board chair, said in a statement released after the FDA’s final rule was published.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration (FDA) plans to scrutinize the safety and efficacy of lab-developed tests — those designed, manufactured, and used in a single laboratory — far more thoroughly in the future.

Under a rule finalized in April, the FDA will treat facilities that develop and use lab tests as manufacturers and regulate tests as medical devices. That means that most lab tests will need an FDA review before going on sale.

The FDA will also impose new quality standards, requiring test manufacturers to report adverse events and create a registry of lab tests under the new rule, which will be phased in over 4 years.

FDA officials have been concerned for years about the reliability of commercial lab tests, which have ballooned into a multibillion-dollar industry.

Consumer groups have long urged the FDA to regulate lab tests more strictly, arguing that the lack of scrutiny allows doctors and patients to be exploited by bad actors such as Theranos, which falsely claimed that its tests could diagnose multiple diseases with a single drop of blood.

“When it comes to some of these tests that doctors are recommending for patients, many doctors are just crossing their fingers and relying on the representation of the company because nobody is checking” to verify a manufacturer’s claims, said Joshua Sharfstein, MD, vice dean for public health practice and community engagement at the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
 

Nearly 12,000 Labs Making Medical Tests

Although the FDA estimates there are nearly 12,000 labs manufacturing medical tests, agency officials said they don’t know how many tests are being marketed. The FDA already requires that home test kits marketed directly to consumers, such as those used to detect COVID-19, get clearance from the agency before being sold.

“There’s plenty of time for industry to get its act together to develop the data that it might need to make a premarket application,” said Peter Lurie, MD, PhD, a former associate commissioner at the FDA. In 2015, Dr. Lurie led a report outlining some of the dangers of unregulated lab tests.

For the average physician who orders lab tests, nothing is going to immediately change because of the final rule, said Dr. Lurie, now president of the Center for Science in the Public Interest, a nonprofit consumer watchdog.

“Tomorrow, this will look just the same as it does today,” Dr. Lurie said. “For the next 3 years, the companies will be scurrying behind the scenes to comply with the early stages of implementation. But most of that will be invisible to the average practitioner.”

Dr. Lurie predicted the FDA will focus its scrutiny on tests that pose the greatest potential risk to patients, such as ones used to diagnose serious diseases or guide treatment for life-threatening conditions. “The least significant tests will likely get very limited, if any, scrutiny,” said Dr. Lurie, adding that the FDA will likely issue guidance about how it plans to define low- and high-risk tests. “My suspicion is that it will be probably a small minority of products that are subject to full premarket approval.”
 

Lab Industry Groups Push Back

But imposing new rules with the potential to affect an industry’s bottom line is no easy task.

The American Clinical Laboratory Association, which represents the lab industry, said in a statement that the FDA rule will “limit access to scores of critical tests, increase healthcare costs, and undermine innovation in new diagnostics.” Another industry group, the Association for Molecular Pathology, has warned of “significant and harmful disruption to laboratory medicine.”

The two associations have filed separate lawsuits, charging that the FDA overstepped the authority granted by Congress. In their lawsuits, groups claim that lab tests are professional services, not manufactured products. The groups noted that the Centers for Medicare & Medicaid Services (CMS) already inspects lab facilities. CMS does not assess the tests’ quality or reliability.

A recent Supreme Court decision could make those lawsuits more likely to succeed, said David Simon, JD, LLM, PhD, an assistant professor of law at the Northeastern University School of Law, Boston, Massachusetts.

In the case of Loper Bright Enterprises v. Raimondo, decided in June, justices overturned a long-standing precedent known as Chevron deference, which required courts to defer to federal agencies when interpreting ambiguous laws. That means that courts no longer have to accept the FDA’s definition of a device, Dr. Simon said.

“Because judges may have more active roles in defining agency authority, federal agencies may have correspondingly less robust roles in policymaking,” Dr. Simon wrote in an editorial coauthored with Michael J. Young, MD, MPhil, of Harvard Medical School, Boston.

The Supreme Court ruling could pressure Congress to more clearly define FDA’s ruling in regulating lab tests, Dr. Simon and Dr. Young wrote.

Members of Congress first introduced a bill to clarify the FDA’s role in regulating lab tests, called the VALID Act, in 2020. The bill stalled and, despite efforts to revive it, still hasn’t passed.

FDA officials have said they remain “open to working with Congress,” noting that any future legislation about lab-developed tests would supersede their current policy.

In an interview, Dr. Simon noted the FDA significantly narrowed the scope of the final rule in response to comments from critics who objected to an earlier version of the policy proposed in 2023. The final rule carves out several categories of tests that won’t need to apply for “premarket review.”

Notably, a “grandfather clause” will allow some lab tests already on the market to continue being sold without undergoing FDA’s premarket review process. In explaining the exemption, FDA officials said they did not want doctors and patients to lose access to tests on which they rely. But Dr. Lurie noted that because the FDA views all these tests as under its jurisdiction, the agency could opt to take a closer look “at a very old device that is causing a problem today.”

The FDA also will exempt tests approved by New York State’s Clinical Laboratory Evaluation Program, which conducts its own stringent reviews. And the FDA will continue to allow hospitals to develop tests for patients within their healthcare system without going through the FDA approval process, if no FDA-approved tests are available.

Hospital-based tests play a critical role in treating infectious diseases, said Amesh Adalja, MD, an infectious diseases specialist and senior scholar at the Johns Hopkins Center for Health Security. For example, a large research hospital treating a patient with cytomegalovirus may need to develop its own test to determine whether the infection is resistant to antiviral drugs, Dr. Adalja said.

“With novel infectious disease outbreaks, researchers are able to move quickly to make diagnostic tests months and months before commercial laboratories are able to get through regulatory processes,” Dr. Adalja said.

To help scientists respond quickly to emergencies, the FDA published special guidance for labs that develop unauthorized lab tests for disease outbreaks.

Medical groups such as the American Hospital Association and Infectious Diseases Society of America remain concerned about the burden of complying with new regulations.

“Many vital tests developed in hospitals and health systems may be subjected to unnecessary and costly paperwork,” said Stacey Hughes, executive vice president of the American Hospital Association, in a statement.

Other groups, such as the American Society of Clinical Oncology, praised the new FDA policy. In comments submitted to the FDA in 2023, the cancer group said it “emphatically supports” requiring lab tests to undergo FDA review.

“We appreciate FDA action to modernize oversight of these tests and are hopeful this rule will increase focus on the need to balance rapid diagnostic innovation with patient safety and access” Everett Vokes, MD, the group’s board chair, said in a statement released after the FDA’s final rule was published.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration (FDA) plans to scrutinize the safety and efficacy of lab-developed tests — those designed, manufactured, and used in a single laboratory — far more thoroughly in the future.

Under a rule finalized in April, the FDA will treat facilities that develop and use lab tests as manufacturers and regulate tests as medical devices. That means that most lab tests will need an FDA review before going on sale.

The FDA will also impose new quality standards, requiring test manufacturers to report adverse events and create a registry of lab tests under the new rule, which will be phased in over 4 years.

FDA officials have been concerned for years about the reliability of commercial lab tests, which have ballooned into a multibillion-dollar industry.

Consumer groups have long urged the FDA to regulate lab tests more strictly, arguing that the lack of scrutiny allows doctors and patients to be exploited by bad actors such as Theranos, which falsely claimed that its tests could diagnose multiple diseases with a single drop of blood.

“When it comes to some of these tests that doctors are recommending for patients, many doctors are just crossing their fingers and relying on the representation of the company because nobody is checking” to verify a manufacturer’s claims, said Joshua Sharfstein, MD, vice dean for public health practice and community engagement at the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
 

Nearly 12,000 Labs Making Medical Tests

Although the FDA estimates there are nearly 12,000 labs manufacturing medical tests, agency officials said they don’t know how many tests are being marketed. The FDA already requires that home test kits marketed directly to consumers, such as those used to detect COVID-19, get clearance from the agency before being sold.

“There’s plenty of time for industry to get its act together to develop the data that it might need to make a premarket application,” said Peter Lurie, MD, PhD, a former associate commissioner at the FDA. In 2015, Dr. Lurie led a report outlining some of the dangers of unregulated lab tests.

For the average physician who orders lab tests, nothing is going to immediately change because of the final rule, said Dr. Lurie, now president of the Center for Science in the Public Interest, a nonprofit consumer watchdog.

“Tomorrow, this will look just the same as it does today,” Dr. Lurie said. “For the next 3 years, the companies will be scurrying behind the scenes to comply with the early stages of implementation. But most of that will be invisible to the average practitioner.”

Dr. Lurie predicted the FDA will focus its scrutiny on tests that pose the greatest potential risk to patients, such as ones used to diagnose serious diseases or guide treatment for life-threatening conditions. “The least significant tests will likely get very limited, if any, scrutiny,” said Dr. Lurie, adding that the FDA will likely issue guidance about how it plans to define low- and high-risk tests. “My suspicion is that it will be probably a small minority of products that are subject to full premarket approval.”
 

Lab Industry Groups Push Back

But imposing new rules with the potential to affect an industry’s bottom line is no easy task.

The American Clinical Laboratory Association, which represents the lab industry, said in a statement that the FDA rule will “limit access to scores of critical tests, increase healthcare costs, and undermine innovation in new diagnostics.” Another industry group, the Association for Molecular Pathology, has warned of “significant and harmful disruption to laboratory medicine.”

The two associations have filed separate lawsuits, charging that the FDA overstepped the authority granted by Congress. In their lawsuits, groups claim that lab tests are professional services, not manufactured products. The groups noted that the Centers for Medicare & Medicaid Services (CMS) already inspects lab facilities. CMS does not assess the tests’ quality or reliability.

A recent Supreme Court decision could make those lawsuits more likely to succeed, said David Simon, JD, LLM, PhD, an assistant professor of law at the Northeastern University School of Law, Boston, Massachusetts.

In the case of Loper Bright Enterprises v. Raimondo, decided in June, justices overturned a long-standing precedent known as Chevron deference, which required courts to defer to federal agencies when interpreting ambiguous laws. That means that courts no longer have to accept the FDA’s definition of a device, Dr. Simon said.

“Because judges may have more active roles in defining agency authority, federal agencies may have correspondingly less robust roles in policymaking,” Dr. Simon wrote in an editorial coauthored with Michael J. Young, MD, MPhil, of Harvard Medical School, Boston.

The Supreme Court ruling could pressure Congress to more clearly define FDA’s ruling in regulating lab tests, Dr. Simon and Dr. Young wrote.

Members of Congress first introduced a bill to clarify the FDA’s role in regulating lab tests, called the VALID Act, in 2020. The bill stalled and, despite efforts to revive it, still hasn’t passed.

FDA officials have said they remain “open to working with Congress,” noting that any future legislation about lab-developed tests would supersede their current policy.

In an interview, Dr. Simon noted the FDA significantly narrowed the scope of the final rule in response to comments from critics who objected to an earlier version of the policy proposed in 2023. The final rule carves out several categories of tests that won’t need to apply for “premarket review.”

Notably, a “grandfather clause” will allow some lab tests already on the market to continue being sold without undergoing FDA’s premarket review process. In explaining the exemption, FDA officials said they did not want doctors and patients to lose access to tests on which they rely. But Dr. Lurie noted that because the FDA views all these tests as under its jurisdiction, the agency could opt to take a closer look “at a very old device that is causing a problem today.”

The FDA also will exempt tests approved by New York State’s Clinical Laboratory Evaluation Program, which conducts its own stringent reviews. And the FDA will continue to allow hospitals to develop tests for patients within their healthcare system without going through the FDA approval process, if no FDA-approved tests are available.

Hospital-based tests play a critical role in treating infectious diseases, said Amesh Adalja, MD, an infectious diseases specialist and senior scholar at the Johns Hopkins Center for Health Security. For example, a large research hospital treating a patient with cytomegalovirus may need to develop its own test to determine whether the infection is resistant to antiviral drugs, Dr. Adalja said.

“With novel infectious disease outbreaks, researchers are able to move quickly to make diagnostic tests months and months before commercial laboratories are able to get through regulatory processes,” Dr. Adalja said.

To help scientists respond quickly to emergencies, the FDA published special guidance for labs that develop unauthorized lab tests for disease outbreaks.

Medical groups such as the American Hospital Association and Infectious Diseases Society of America remain concerned about the burden of complying with new regulations.

“Many vital tests developed in hospitals and health systems may be subjected to unnecessary and costly paperwork,” said Stacey Hughes, executive vice president of the American Hospital Association, in a statement.

Other groups, such as the American Society of Clinical Oncology, praised the new FDA policy. In comments submitted to the FDA in 2023, the cancer group said it “emphatically supports” requiring lab tests to undergo FDA review.

“We appreciate FDA action to modernize oversight of these tests and are hopeful this rule will increase focus on the need to balance rapid diagnostic innovation with patient safety and access” Everett Vokes, MD, the group’s board chair, said in a statement released after the FDA’s final rule was published.

A version of this article first appeared on Medscape.com.

It’s well known that the United States enjoys the dubious distinction of having the worst maternal morbidity and mortality rates among industrialized nations. Maternal mortality in this country increased by 14% from 2018 to 2020, according to the Centers for Disease Control and Prevention’s National Center for Health Statistics.

But a current trend of engaging birth doulas — nonmedical guides offering continuous one-on-one physical and psychological support in the pre-, peri,- and postnatal periods — may be poised to brighten that dismal statistical landscape.

Recent research has shown that mothers matched with a doula are less likely to have a low birth weight baby, less likely to experience a birth complication, and significantly more likely to initiate breastfeeding.

Doula services — even delivered digitally — are seen to lower healthcare costs, reduce cesarean sections, decrease maternal anxiety and depression, and improve communication between healthcare providers and low-income, racially/ethnically diverse pregnant women. Doulas can be especially helpful for mothers dealing with the psychological fallout of miscarriage or stillbirth. They can guide patients in the postpartum period, when problems can arise and when some mothers are lost to medical follow-up, and provide an ongoing source of patient information for the ob.gyn.

“Research has shown that in addition to better outcomes, doula care can shorten labor time and increase patient satisfaction,” said ob.gyn. Layan Alrahmani, MD, in an interview. A maternal-fetal medicine specialist with a focus on high-risk pregnancies among low-income women at Loyola Medicine in Maywood, Illinois, Dr. Alrahmani welcomes doulas to her patients’ antenatal visits.

“Many of my patients who are looking to avoid an epidural will work with a labor doula, in order to stay home as long as possible and to have one-on-one coaching through the pain as things progress,” said Susan Rothenberg, MD, an assistant professor of obstetrics, gynecology, and reproductive science at the Icahn School of Medicine at Mount Sinai and an ob/gyn at Mount Sinai Downtown Union Square in New York City. She added, “When a woman’s partner is squeamish or potentially unavailable, a labor doula can be a great option.”

Another ob.gyn. who enthusiastically embraces doula care is L. Joy Baker, MD, who practices in LaGrange, Georgia, and is affiliated with Wellstar West Georgia Medical Center. “I love it when my patients have a doula. A doula answers a patient’s questions throughout the pregnancy and amplifies the mother’s voice in the medical system and the clinical setting,” Dr. Baker told this news organization.

“They provide important details on patients’ food, housing, and transportation status when the mothers themselves would not bring those up in a short appointment with their doctors,” she said. Dr. Baker called for more recognition of their merit, especially for first-time and high-risk moms.

Efua B. Leke, MD, MPH, an assistant professor at Baylor College of Medicine and chief of obstetrics at Ben Taub Hospital in Houston, Texas, also believes a major benefit of doulas is improved flow of information. “We know that having doulas participate in maternal care can ease communication between pregnant and parturient mothers and their clinical team,” Dr. Leke said. “This is especially important for under-resourced pregnant women for whom morbidity tends to be disparately higher.”

Doulas can also take pressure off embattled ob.gyn. clinical staff. “Our volume of patients is huge, so we have to keep appointments brief,” Dr. Baker said. “The US is currently 8000 ob.gyn.s short, and to make matters worse, we’re seeing more and more obstetrical care deserts.”

Still largely underutilized, doula care is seen by its proponents as important in light of the drastic shortage of ob.gyn.s and the shrinking presence of maternity care in many US counties.

According to a recent March of Dimes report, access to maternity care is waning, with more than 35% of US counties offering no community obstetrical care and 52% providing no maternity care in local hospitals. That translates to long distances and extended travel time for mothers seeking care.
 

Growth Remains Slow

Although many believe doulas could become part of the solution to the lack of access to maternity care, their acceptance seems to be slow growing. In a 2012 national survey by Declercq and associates, about 6% of mothers used a doula during childbirth, up from 3% in a 2006 national survey. Of those who were familiar with but lacking doula care, just 27% would have chosen to have this service.

“I’d estimate that doulas are still involved in only about 6%-8% of births,” said Shaconna Haley, MA, a certified holistic doula and doula trainer in Atlanta, Georgia.

And are there enough practicing doulas in the United States to put a dent in the current shortfall in pregnancy care? Although no reliable estimate of their numbers exists, a centralized online doula registration service listed 9000 registered practitioners in 2018. Contrast that with the approximately 3.6 million live births in 2023.
 

Potential for Friction?

Although generally seen as benign and helpful, the presence of a doula can add another layer of people for hard-pressed medical staff to deal with. Can their attendance occasionally lead to an adversarial encounter? Yes, said Dr. Baker, especially in the case of assertive questioning or suggestions directed at medical staff. “There can be some mistrust on the part of clinicians when nonmedical persons start raising concerns and asking questions. Staff can get a little prickly at this.”

In the view of Melissa A. Simon, MD, MPH, a professor of obstetrics and gynecology, preventive medicine, and medical social sciences at Northwestern University Feinberg School of Medicine in Chicago, Illinois, simple, preventable communication breakdown is often the cause of occasional antagonism. “As in all team care approaches, it’s helpful to have upfront conversations with the birthing person, the doula, and any care team members or support people who will be present in the birthing room. These conversations should be about expectations.”

According to Ms. Haley, “As long as the focus stays firmly on the client/patient and not on the other team members, there should be no friction. Medical staff should be aware there will be a doula in attendance and ideally there should be a collaborative team and plan in place before the birth.” 

In Dr. Leke’s experience, doulas do not hinder the medical team as long as clinical roles are well clarified and the patient is engaged in her care plan. “Friction can occur when doulas are functioning outside of their scope of practice, such as speaking to the healthcare team on behalf of the mother instead empowering the mother to speak up herself,” she said. “Or, when the healthcare team doesn’t understand the doula’s scope of practice or recognize the doula as a member of the team.” 

Added Dr. Rothenberg, “I’ve occasionally run into doulas who imagine I have an ulterior motive when making recommendations to patients when that’s completely untrue. It’s common for women to decide to become doulas because they didn’t feel listened to during their own birthing experience, and for a few of them, it’s hard to not project that onto their clients’ labor situations, creating conflict where it doesn’t need to exist.”
 

Barriers and Challenges 

Unfortunately, the barriers of cost and access remain high for pregnant and birthing mothers from lower socioeconomic echelons who have no or limited insurance. “There also are very few multilingual doulas or doulas from diverse racial-ethnic backgrounds and identities,” Dr. Simon pointed out.
Yet by all indications, Medicaid members who receive doula services experience positive maternal outcomes, even those at higher risk for pregnancy complications.

As for Medicaid coverage of doula services, in a recent Centers for Medicare & Medicaid Services report, just 11 state Medicaid programs were reimbursing doula services, whereas an additional five were in the process of implementing reimbursement.

Doula care is not covered by all private insurance plans either, Dr. Simon said. “Although there are maternity care bundles with payment models that help integrate doula care, and there are ways to use your flexible spending account to cover it.”

Some hospitals may undertake independent initiatives. Dr. Baker’s center is offering antenatal and peripartum doula support for under-resourced mothers thanks to a Health Resources and Services Administration grant.* 

But for now, doula services are largely limited to middle- and high-income women able to afford the associated out-of-pocket costs. These mothers are disproportionately White, and the doulas serving them tend to be of the same race and socioeconomic class.

The Future

Dr. Simon foresees an optimal scenario in which a team of doulas works with all birthing persons on a hospital labor floor as well as with a team of clinicians. “It takes a true team approach to ensure an optimal birthing experience and optimal birth outcomes,” she said.

Despite the many challenges ahead, doulas will probably become a permanent fixture in pregnancy, birth, and postpartum care, said Dr. Baker. “Doula care is going to be a game changer, and obstetricians welcome doulas to the obstetrical care team.” 

Dr. Alrahmani, Dr. Baker, Ms. Haley, Dr. Leke, Dr. Rothenberg, and Dr. Simon declared no conflicts of interest relevant to their comments.

*This story was updated on October 1, 2024.

A version of this article first appeared on Medscape.com.

It’s well known that the United States enjoys the dubious distinction of having the worst maternal morbidity and mortality rates among industrialized nations. Maternal mortality in this country increased by 14% from 2018 to 2020, according to the Centers for Disease Control and Prevention’s National Center for Health Statistics.

But a current trend of engaging birth doulas — nonmedical guides offering continuous one-on-one physical and psychological support in the pre-, peri,- and postnatal periods — may be poised to brighten that dismal statistical landscape.

Recent research has shown that mothers matched with a doula are less likely to have a low birth weight baby, less likely to experience a birth complication, and significantly more likely to initiate breastfeeding.

Doula services — even delivered digitally — are seen to lower healthcare costs, reduce cesarean sections, decrease maternal anxiety and depression, and improve communication between healthcare providers and low-income, racially/ethnically diverse pregnant women. Doulas can be especially helpful for mothers dealing with the psychological fallout of miscarriage or stillbirth. They can guide patients in the postpartum period, when problems can arise and when some mothers are lost to medical follow-up, and provide an ongoing source of patient information for the ob.gyn.

“Research has shown that in addition to better outcomes, doula care can shorten labor time and increase patient satisfaction,” said ob.gyn. Layan Alrahmani, MD, in an interview. A maternal-fetal medicine specialist with a focus on high-risk pregnancies among low-income women at Loyola Medicine in Maywood, Illinois, Dr. Alrahmani welcomes doulas to her patients’ antenatal visits.

“Many of my patients who are looking to avoid an epidural will work with a labor doula, in order to stay home as long as possible and to have one-on-one coaching through the pain as things progress,” said Susan Rothenberg, MD, an assistant professor of obstetrics, gynecology, and reproductive science at the Icahn School of Medicine at Mount Sinai and an ob/gyn at Mount Sinai Downtown Union Square in New York City. She added, “When a woman’s partner is squeamish or potentially unavailable, a labor doula can be a great option.”

Another ob.gyn. who enthusiastically embraces doula care is L. Joy Baker, MD, who practices in LaGrange, Georgia, and is affiliated with Wellstar West Georgia Medical Center. “I love it when my patients have a doula. A doula answers a patient’s questions throughout the pregnancy and amplifies the mother’s voice in the medical system and the clinical setting,” Dr. Baker told this news organization.

“They provide important details on patients’ food, housing, and transportation status when the mothers themselves would not bring those up in a short appointment with their doctors,” she said. Dr. Baker called for more recognition of their merit, especially for first-time and high-risk moms.

Efua B. Leke, MD, MPH, an assistant professor at Baylor College of Medicine and chief of obstetrics at Ben Taub Hospital in Houston, Texas, also believes a major benefit of doulas is improved flow of information. “We know that having doulas participate in maternal care can ease communication between pregnant and parturient mothers and their clinical team,” Dr. Leke said. “This is especially important for under-resourced pregnant women for whom morbidity tends to be disparately higher.”

Doulas can also take pressure off embattled ob.gyn. clinical staff. “Our volume of patients is huge, so we have to keep appointments brief,” Dr. Baker said. “The US is currently 8000 ob.gyn.s short, and to make matters worse, we’re seeing more and more obstetrical care deserts.”

Still largely underutilized, doula care is seen by its proponents as important in light of the drastic shortage of ob.gyn.s and the shrinking presence of maternity care in many US counties.

According to a recent March of Dimes report, access to maternity care is waning, with more than 35% of US counties offering no community obstetrical care and 52% providing no maternity care in local hospitals. That translates to long distances and extended travel time for mothers seeking care.
 

Growth Remains Slow

Although many believe doulas could become part of the solution to the lack of access to maternity care, their acceptance seems to be slow growing. In a 2012 national survey by Declercq and associates, about 6% of mothers used a doula during childbirth, up from 3% in a 2006 national survey. Of those who were familiar with but lacking doula care, just 27% would have chosen to have this service.

“I’d estimate that doulas are still involved in only about 6%-8% of births,” said Shaconna Haley, MA, a certified holistic doula and doula trainer in Atlanta, Georgia.

And are there enough practicing doulas in the United States to put a dent in the current shortfall in pregnancy care? Although no reliable estimate of their numbers exists, a centralized online doula registration service listed 9000 registered practitioners in 2018. Contrast that with the approximately 3.6 million live births in 2023.
 

Potential for Friction?

Although generally seen as benign and helpful, the presence of a doula can add another layer of people for hard-pressed medical staff to deal with. Can their attendance occasionally lead to an adversarial encounter? Yes, said Dr. Baker, especially in the case of assertive questioning or suggestions directed at medical staff. “There can be some mistrust on the part of clinicians when nonmedical persons start raising concerns and asking questions. Staff can get a little prickly at this.”

In the view of Melissa A. Simon, MD, MPH, a professor of obstetrics and gynecology, preventive medicine, and medical social sciences at Northwestern University Feinberg School of Medicine in Chicago, Illinois, simple, preventable communication breakdown is often the cause of occasional antagonism. “As in all team care approaches, it’s helpful to have upfront conversations with the birthing person, the doula, and any care team members or support people who will be present in the birthing room. These conversations should be about expectations.”

According to Ms. Haley, “As long as the focus stays firmly on the client/patient and not on the other team members, there should be no friction. Medical staff should be aware there will be a doula in attendance and ideally there should be a collaborative team and plan in place before the birth.” 

In Dr. Leke’s experience, doulas do not hinder the medical team as long as clinical roles are well clarified and the patient is engaged in her care plan. “Friction can occur when doulas are functioning outside of their scope of practice, such as speaking to the healthcare team on behalf of the mother instead empowering the mother to speak up herself,” she said. “Or, when the healthcare team doesn’t understand the doula’s scope of practice or recognize the doula as a member of the team.” 

Added Dr. Rothenberg, “I’ve occasionally run into doulas who imagine I have an ulterior motive when making recommendations to patients when that’s completely untrue. It’s common for women to decide to become doulas because they didn’t feel listened to during their own birthing experience, and for a few of them, it’s hard to not project that onto their clients’ labor situations, creating conflict where it doesn’t need to exist.”
 

Barriers and Challenges 

Unfortunately, the barriers of cost and access remain high for pregnant and birthing mothers from lower socioeconomic echelons who have no or limited insurance. “There also are very few multilingual doulas or doulas from diverse racial-ethnic backgrounds and identities,” Dr. Simon pointed out.
Yet by all indications, Medicaid members who receive doula services experience positive maternal outcomes, even those at higher risk for pregnancy complications.

As for Medicaid coverage of doula services, in a recent Centers for Medicare & Medicaid Services report, just 11 state Medicaid programs were reimbursing doula services, whereas an additional five were in the process of implementing reimbursement.

Doula care is not covered by all private insurance plans either, Dr. Simon said. “Although there are maternity care bundles with payment models that help integrate doula care, and there are ways to use your flexible spending account to cover it.”

Some hospitals may undertake independent initiatives. Dr. Baker’s center is offering antenatal and peripartum doula support for under-resourced mothers thanks to a Health Resources and Services Administration grant.* 

But for now, doula services are largely limited to middle- and high-income women able to afford the associated out-of-pocket costs. These mothers are disproportionately White, and the doulas serving them tend to be of the same race and socioeconomic class.

The Future

Dr. Simon foresees an optimal scenario in which a team of doulas works with all birthing persons on a hospital labor floor as well as with a team of clinicians. “It takes a true team approach to ensure an optimal birthing experience and optimal birth outcomes,” she said.

Despite the many challenges ahead, doulas will probably become a permanent fixture in pregnancy, birth, and postpartum care, said Dr. Baker. “Doula care is going to be a game changer, and obstetricians welcome doulas to the obstetrical care team.” 

Dr. Alrahmani, Dr. Baker, Ms. Haley, Dr. Leke, Dr. Rothenberg, and Dr. Simon declared no conflicts of interest relevant to their comments.

*This story was updated on October 1, 2024.

A version of this article first appeared on Medscape.com.

It’s well known that the United States enjoys the dubious distinction of having the worst maternal morbidity and mortality rates among industrialized nations. Maternal mortality in this country increased by 14% from 2018 to 2020, according to the Centers for Disease Control and Prevention’s National Center for Health Statistics.

But a current trend of engaging birth doulas — nonmedical guides offering continuous one-on-one physical and psychological support in the pre-, peri,- and postnatal periods — may be poised to brighten that dismal statistical landscape.

Recent research has shown that mothers matched with a doula are less likely to have a low birth weight baby, less likely to experience a birth complication, and significantly more likely to initiate breastfeeding.

Doula services — even delivered digitally — are seen to lower healthcare costs, reduce cesarean sections, decrease maternal anxiety and depression, and improve communication between healthcare providers and low-income, racially/ethnically diverse pregnant women. Doulas can be especially helpful for mothers dealing with the psychological fallout of miscarriage or stillbirth. They can guide patients in the postpartum period, when problems can arise and when some mothers are lost to medical follow-up, and provide an ongoing source of patient information for the ob.gyn.

“Research has shown that in addition to better outcomes, doula care can shorten labor time and increase patient satisfaction,” said ob.gyn. Layan Alrahmani, MD, in an interview. A maternal-fetal medicine specialist with a focus on high-risk pregnancies among low-income women at Loyola Medicine in Maywood, Illinois, Dr. Alrahmani welcomes doulas to her patients’ antenatal visits.

“Many of my patients who are looking to avoid an epidural will work with a labor doula, in order to stay home as long as possible and to have one-on-one coaching through the pain as things progress,” said Susan Rothenberg, MD, an assistant professor of obstetrics, gynecology, and reproductive science at the Icahn School of Medicine at Mount Sinai and an ob/gyn at Mount Sinai Downtown Union Square in New York City. She added, “When a woman’s partner is squeamish or potentially unavailable, a labor doula can be a great option.”

Another ob.gyn. who enthusiastically embraces doula care is L. Joy Baker, MD, who practices in LaGrange, Georgia, and is affiliated with Wellstar West Georgia Medical Center. “I love it when my patients have a doula. A doula answers a patient’s questions throughout the pregnancy and amplifies the mother’s voice in the medical system and the clinical setting,” Dr. Baker told this news organization.

“They provide important details on patients’ food, housing, and transportation status when the mothers themselves would not bring those up in a short appointment with their doctors,” she said. Dr. Baker called for more recognition of their merit, especially for first-time and high-risk moms.

Efua B. Leke, MD, MPH, an assistant professor at Baylor College of Medicine and chief of obstetrics at Ben Taub Hospital in Houston, Texas, also believes a major benefit of doulas is improved flow of information. “We know that having doulas participate in maternal care can ease communication between pregnant and parturient mothers and their clinical team,” Dr. Leke said. “This is especially important for under-resourced pregnant women for whom morbidity tends to be disparately higher.”

Doulas can also take pressure off embattled ob.gyn. clinical staff. “Our volume of patients is huge, so we have to keep appointments brief,” Dr. Baker said. “The US is currently 8000 ob.gyn.s short, and to make matters worse, we’re seeing more and more obstetrical care deserts.”

Still largely underutilized, doula care is seen by its proponents as important in light of the drastic shortage of ob.gyn.s and the shrinking presence of maternity care in many US counties.

According to a recent March of Dimes report, access to maternity care is waning, with more than 35% of US counties offering no community obstetrical care and 52% providing no maternity care in local hospitals. That translates to long distances and extended travel time for mothers seeking care.
 

Growth Remains Slow

Although many believe doulas could become part of the solution to the lack of access to maternity care, their acceptance seems to be slow growing. In a 2012 national survey by Declercq and associates, about 6% of mothers used a doula during childbirth, up from 3% in a 2006 national survey. Of those who were familiar with but lacking doula care, just 27% would have chosen to have this service.

“I’d estimate that doulas are still involved in only about 6%-8% of births,” said Shaconna Haley, MA, a certified holistic doula and doula trainer in Atlanta, Georgia.

And are there enough practicing doulas in the United States to put a dent in the current shortfall in pregnancy care? Although no reliable estimate of their numbers exists, a centralized online doula registration service listed 9000 registered practitioners in 2018. Contrast that with the approximately 3.6 million live births in 2023.
 

Potential for Friction?

Although generally seen as benign and helpful, the presence of a doula can add another layer of people for hard-pressed medical staff to deal with. Can their attendance occasionally lead to an adversarial encounter? Yes, said Dr. Baker, especially in the case of assertive questioning or suggestions directed at medical staff. “There can be some mistrust on the part of clinicians when nonmedical persons start raising concerns and asking questions. Staff can get a little prickly at this.”

In the view of Melissa A. Simon, MD, MPH, a professor of obstetrics and gynecology, preventive medicine, and medical social sciences at Northwestern University Feinberg School of Medicine in Chicago, Illinois, simple, preventable communication breakdown is often the cause of occasional antagonism. “As in all team care approaches, it’s helpful to have upfront conversations with the birthing person, the doula, and any care team members or support people who will be present in the birthing room. These conversations should be about expectations.”

According to Ms. Haley, “As long as the focus stays firmly on the client/patient and not on the other team members, there should be no friction. Medical staff should be aware there will be a doula in attendance and ideally there should be a collaborative team and plan in place before the birth.” 

In Dr. Leke’s experience, doulas do not hinder the medical team as long as clinical roles are well clarified and the patient is engaged in her care plan. “Friction can occur when doulas are functioning outside of their scope of practice, such as speaking to the healthcare team on behalf of the mother instead empowering the mother to speak up herself,” she said. “Or, when the healthcare team doesn’t understand the doula’s scope of practice or recognize the doula as a member of the team.” 

Added Dr. Rothenberg, “I’ve occasionally run into doulas who imagine I have an ulterior motive when making recommendations to patients when that’s completely untrue. It’s common for women to decide to become doulas because they didn’t feel listened to during their own birthing experience, and for a few of them, it’s hard to not project that onto their clients’ labor situations, creating conflict where it doesn’t need to exist.”
 

Barriers and Challenges 

Unfortunately, the barriers of cost and access remain high for pregnant and birthing mothers from lower socioeconomic echelons who have no or limited insurance. “There also are very few multilingual doulas or doulas from diverse racial-ethnic backgrounds and identities,” Dr. Simon pointed out.
Yet by all indications, Medicaid members who receive doula services experience positive maternal outcomes, even those at higher risk for pregnancy complications.

As for Medicaid coverage of doula services, in a recent Centers for Medicare & Medicaid Services report, just 11 state Medicaid programs were reimbursing doula services, whereas an additional five were in the process of implementing reimbursement.

Doula care is not covered by all private insurance plans either, Dr. Simon said. “Although there are maternity care bundles with payment models that help integrate doula care, and there are ways to use your flexible spending account to cover it.”

Some hospitals may undertake independent initiatives. Dr. Baker’s center is offering antenatal and peripartum doula support for under-resourced mothers thanks to a Health Resources and Services Administration grant.* 

But for now, doula services are largely limited to middle- and high-income women able to afford the associated out-of-pocket costs. These mothers are disproportionately White, and the doulas serving them tend to be of the same race and socioeconomic class.

The Future

Dr. Simon foresees an optimal scenario in which a team of doulas works with all birthing persons on a hospital labor floor as well as with a team of clinicians. “It takes a true team approach to ensure an optimal birthing experience and optimal birth outcomes,” she said.

Despite the many challenges ahead, doulas will probably become a permanent fixture in pregnancy, birth, and postpartum care, said Dr. Baker. “Doula care is going to be a game changer, and obstetricians welcome doulas to the obstetrical care team.” 

Dr. Alrahmani, Dr. Baker, Ms. Haley, Dr. Leke, Dr. Rothenberg, and Dr. Simon declared no conflicts of interest relevant to their comments.

*This story was updated on October 1, 2024.

A version of this article first appeared on Medscape.com.

TOPLINE:

Diabetes and prediabetes are associated with accelerated brain aging with brain age gaps of 2.29 and 0.50 years, respectively. This association is more pronounced in men and those with poor cardiometabolic health but may be mitigated by a healthy lifestyle.

METHODOLOGY:

• Diabetes is a known risk factor for cognitive impairment, dementia, and global brain atrophy but conflicting results have been reported for prediabetes, and it’s unknown whether a healthy lifestyle can counteract the negative impact of prediabetes.
• Researchers examined the cross-sectional and longitudinal relationship between hyperglycemia and brain aging, as well as the potential mitigating effect of a healthy lifestyle in 31,229 dementia-free adults (mean age, 54.8 years; 53% women) from the UK Biobank, including 13,518 participants with prediabetes and 1149 with diabetes.
• The glycemic status of the participants was determined by their medical history, medication use, and A1c levels.
• The brain age gap was calculated as a difference between chronologic age and brain age estimated from MRI data from six modalities vs several hundred brain MRI phenotypes that were modeled from a subset of healthy individuals.
• The role of sex, cardiometabolic risk factors, and a healthy lifestyle and their association with brain age was also explored, with a healthy lifestyle defined as never smoking, no or light or moderate alcohol consumption, and high physical activity.

TAKEAWAY:

• Prediabetes and diabetes were associated with a higher brain age gap than normoglycemia (beta-coefficient, 0.22 and 2.01; 95% CI, 0.10-0.34 and 1.70-2.32, respectively), and diabetes was more pronounced in men vs women and those with a higher vs lower burden of cardiometabolic risk factors.
• The brain ages of those with prediabetes and diabetes were 0.50 years and 2.29 years older on average than their respective chronologic ages.
• In an exploratory longitudinal analysis of the 2414 participants with two brain MRI scans, diabetes was linked to a 0.27-year annual increase in the brain age gap, and higher A1c, but not prediabetes, was associated with a significant increase in brain age gap.
• A healthy lifestyle attenuated the association between diabetes and a higher brain age gap (P = .003), reducing it by 1.68 years, also with a significant interaction between glycemic status and lifestyle.

IN PRACTICE:

“Our findings highlight diabetes and prediabetes as ideal targets for lifestyle-based interventions to promote brain health,” the authors wrote.

SOURCE:

This study, led by Abigail Dove, Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden, was published online in Diabetes Care.

LIMITATIONS:

The generalizability of the findings was limited due to a healthy volunteer bias in the UK Biobank. A high proportion of missing data prevented the inclusion of diet in the healthy lifestyle construct. Reverse causality may be possible as an older brain may contribute to the development of prediabetes by making it more difficult to manage medical conditions and adhere to a healthy lifestyle. A1c levels were measured only at baseline, preventing the assessment of changes in glycemic control over time.

DISCLOSURES:

The authors reported receiving funding from the Swedish Research Council; Swedish Research Council for Health, Working Life and Welfare; Karolinska Institutet Board of Research; Riksbankens Jubileumsfond; Marianne and Marcus Wallenberg Foundation; Alzheimerfonden; and Demensfonden. They declared no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Diabetes and prediabetes are associated with accelerated brain aging with brain age gaps of 2.29 and 0.50 years, respectively. This association is more pronounced in men and those with poor cardiometabolic health but may be mitigated by a healthy lifestyle.

METHODOLOGY:

• Diabetes is a known risk factor for cognitive impairment, dementia, and global brain atrophy but conflicting results have been reported for prediabetes, and it’s unknown whether a healthy lifestyle can counteract the negative impact of prediabetes.
• Researchers examined the cross-sectional and longitudinal relationship between hyperglycemia and brain aging, as well as the potential mitigating effect of a healthy lifestyle in 31,229 dementia-free adults (mean age, 54.8 years; 53% women) from the UK Biobank, including 13,518 participants with prediabetes and 1149 with diabetes.
• The glycemic status of the participants was determined by their medical history, medication use, and A1c levels.
• The brain age gap was calculated as a difference between chronologic age and brain age estimated from MRI data from six modalities vs several hundred brain MRI phenotypes that were modeled from a subset of healthy individuals.
• The role of sex, cardiometabolic risk factors, and a healthy lifestyle and their association with brain age was also explored, with a healthy lifestyle defined as never smoking, no or light or moderate alcohol consumption, and high physical activity.

TAKEAWAY:

• Prediabetes and diabetes were associated with a higher brain age gap than normoglycemia (beta-coefficient, 0.22 and 2.01; 95% CI, 0.10-0.34 and 1.70-2.32, respectively), and diabetes was more pronounced in men vs women and those with a higher vs lower burden of cardiometabolic risk factors.
• The brain ages of those with prediabetes and diabetes were 0.50 years and 2.29 years older on average than their respective chronologic ages.
• In an exploratory longitudinal analysis of the 2414 participants with two brain MRI scans, diabetes was linked to a 0.27-year annual increase in the brain age gap, and higher A1c, but not prediabetes, was associated with a significant increase in brain age gap.
• A healthy lifestyle attenuated the association between diabetes and a higher brain age gap (P = .003), reducing it by 1.68 years, also with a significant interaction between glycemic status and lifestyle.

IN PRACTICE:

“Our findings highlight diabetes and prediabetes as ideal targets for lifestyle-based interventions to promote brain health,” the authors wrote.

SOURCE:

This study, led by Abigail Dove, Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden, was published online in Diabetes Care.

LIMITATIONS:

The generalizability of the findings was limited due to a healthy volunteer bias in the UK Biobank. A high proportion of missing data prevented the inclusion of diet in the healthy lifestyle construct. Reverse causality may be possible as an older brain may contribute to the development of prediabetes by making it more difficult to manage medical conditions and adhere to a healthy lifestyle. A1c levels were measured only at baseline, preventing the assessment of changes in glycemic control over time.

DISCLOSURES:

The authors reported receiving funding from the Swedish Research Council; Swedish Research Council for Health, Working Life and Welfare; Karolinska Institutet Board of Research; Riksbankens Jubileumsfond; Marianne and Marcus Wallenberg Foundation; Alzheimerfonden; and Demensfonden. They declared no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Diabetes and prediabetes are associated with accelerated brain aging with brain age gaps of 2.29 and 0.50 years, respectively. This association is more pronounced in men and those with poor cardiometabolic health but may be mitigated by a healthy lifestyle.

METHODOLOGY:

• Diabetes is a known risk factor for cognitive impairment, dementia, and global brain atrophy but conflicting results have been reported for prediabetes, and it’s unknown whether a healthy lifestyle can counteract the negative impact of prediabetes.
• Researchers examined the cross-sectional and longitudinal relationship between hyperglycemia and brain aging, as well as the potential mitigating effect of a healthy lifestyle in 31,229 dementia-free adults (mean age, 54.8 years; 53% women) from the UK Biobank, including 13,518 participants with prediabetes and 1149 with diabetes.
• The glycemic status of the participants was determined by their medical history, medication use, and A1c levels.
• The brain age gap was calculated as a difference between chronologic age and brain age estimated from MRI data from six modalities vs several hundred brain MRI phenotypes that were modeled from a subset of healthy individuals.
• The role of sex, cardiometabolic risk factors, and a healthy lifestyle and their association with brain age was also explored, with a healthy lifestyle defined as never smoking, no or light or moderate alcohol consumption, and high physical activity.

TAKEAWAY:

• Prediabetes and diabetes were associated with a higher brain age gap than normoglycemia (beta-coefficient, 0.22 and 2.01; 95% CI, 0.10-0.34 and 1.70-2.32, respectively), and diabetes was more pronounced in men vs women and those with a higher vs lower burden of cardiometabolic risk factors.
• The brain ages of those with prediabetes and diabetes were 0.50 years and 2.29 years older on average than their respective chronologic ages.
• In an exploratory longitudinal analysis of the 2414 participants with two brain MRI scans, diabetes was linked to a 0.27-year annual increase in the brain age gap, and higher A1c, but not prediabetes, was associated with a significant increase in brain age gap.
• A healthy lifestyle attenuated the association between diabetes and a higher brain age gap (P = .003), reducing it by 1.68 years, also with a significant interaction between glycemic status and lifestyle.

IN PRACTICE:

“Our findings highlight diabetes and prediabetes as ideal targets for lifestyle-based interventions to promote brain health,” the authors wrote.

SOURCE:

This study, led by Abigail Dove, Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden, was published online in Diabetes Care.

LIMITATIONS:

The generalizability of the findings was limited due to a healthy volunteer bias in the UK Biobank. A high proportion of missing data prevented the inclusion of diet in the healthy lifestyle construct. Reverse causality may be possible as an older brain may contribute to the development of prediabetes by making it more difficult to manage medical conditions and adhere to a healthy lifestyle. A1c levels were measured only at baseline, preventing the assessment of changes in glycemic control over time.

DISCLOSURES:

The authors reported receiving funding from the Swedish Research Council; Swedish Research Council for Health, Working Life and Welfare; Karolinska Institutet Board of Research; Riksbankens Jubileumsfond; Marianne and Marcus Wallenberg Foundation; Alzheimerfonden; and Demensfonden. They declared no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Higher body mass index (BMI) in both partners is linked to lower fecundability and increased subfertility. Overweight and obesity in women are associated with higher odds of miscarriage.

METHODOLOGY:

• Researchers conducted a population-based prospective cohort study in Rotterdam, the Netherlands, from August 9, 2017, to July 1, 2021.
• A total of 3604 women and their partners were included, with follow-up until birth.
• BMI was measured in preconception or early pregnancy, and outcomes included fecundability, subfertility, and miscarriage.
• Fecundability was defined as the probability of conceiving within 1 month and subfertility as time to pregnancy or duration of actively pursuing pregnancy of more than 12 months or use of assisted reproductive technology.
• Miscarriage was defined as pregnancy loss before 22 weeks of gestation.

TAKEAWAY:

• Higher BMI in women and men was associated with lower fecundability: For every unit increase in BMI, fecundability decreased (women, 0.98; 95% CI, 0.97-0.99; men, 0.99; 95% CI, 0.98-1.00).
• Women with overweight (0.88; 95% CI, 0.80-0.98) and obesity (0.72; 95% CI, 0.63-0.82) had lower fecundability than women with normal weight.
• Overweight (1.35; 95% CI, 1.11-1.63) and obesity (1.67; 95% CI, 1.30-2.13) in women were associated with increased odds of subfertility.
• Obesity in men was associated with increased odds of subfertility (1.69; 95% CI, 1.24-2.31).

IN PRACTICE:

“We observed in this cohort study that BMI outside of the normal category in women and men was associated with lower fecundability, subfertility, and increased odds of miscarriage. Optimizing BMI from the preconception period onward in women and men might be an important strategy to improve fertility and pregnancy outcomes,” wrote the authors of the study.

SOURCE:

The study was led by Aline J. Boxem, MD, and Vincent W. V. Jaddoe, MD, PhD, The Generation R Study Group, Erasmus University Medical Centre in Rotterdam, the Netherlands. It was published online in JAMA Network Open.

LIMITATIONS:

The study’s generalizability may be affected by differences between included and excluded participants, who were younger and had a higher BMI. The accuracy of time-to-pregnancy duration may have been impacted by retrospectively answered questionnaires. Residual confounding might still be an issue due to the observational nature of the study.

DISCLOSURES:

Dr. Boxem and Dr. Jaddoe disclosed receiving grants from the Erasmus University Medical Centre, the Erasmus University Rotterdam, and the Netherlands Organisation for Health Research and Development. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Higher body mass index (BMI) in both partners is linked to lower fecundability and increased subfertility. Overweight and obesity in women are associated with higher odds of miscarriage.

METHODOLOGY:

• Researchers conducted a population-based prospective cohort study in Rotterdam, the Netherlands, from August 9, 2017, to July 1, 2021.
• A total of 3604 women and their partners were included, with follow-up until birth.
• BMI was measured in preconception or early pregnancy, and outcomes included fecundability, subfertility, and miscarriage.
• Fecundability was defined as the probability of conceiving within 1 month and subfertility as time to pregnancy or duration of actively pursuing pregnancy of more than 12 months or use of assisted reproductive technology.
• Miscarriage was defined as pregnancy loss before 22 weeks of gestation.

TAKEAWAY:

• Higher BMI in women and men was associated with lower fecundability: For every unit increase in BMI, fecundability decreased (women, 0.98; 95% CI, 0.97-0.99; men, 0.99; 95% CI, 0.98-1.00).
• Women with overweight (0.88; 95% CI, 0.80-0.98) and obesity (0.72; 95% CI, 0.63-0.82) had lower fecundability than women with normal weight.
• Overweight (1.35; 95% CI, 1.11-1.63) and obesity (1.67; 95% CI, 1.30-2.13) in women were associated with increased odds of subfertility.
• Obesity in men was associated with increased odds of subfertility (1.69; 95% CI, 1.24-2.31).

IN PRACTICE:

“We observed in this cohort study that BMI outside of the normal category in women and men was associated with lower fecundability, subfertility, and increased odds of miscarriage. Optimizing BMI from the preconception period onward in women and men might be an important strategy to improve fertility and pregnancy outcomes,” wrote the authors of the study.

SOURCE:

The study was led by Aline J. Boxem, MD, and Vincent W. V. Jaddoe, MD, PhD, The Generation R Study Group, Erasmus University Medical Centre in Rotterdam, the Netherlands. It was published online in JAMA Network Open.

LIMITATIONS:

The study’s generalizability may be affected by differences between included and excluded participants, who were younger and had a higher BMI. The accuracy of time-to-pregnancy duration may have been impacted by retrospectively answered questionnaires. Residual confounding might still be an issue due to the observational nature of the study.

DISCLOSURES:

Dr. Boxem and Dr. Jaddoe disclosed receiving grants from the Erasmus University Medical Centre, the Erasmus University Rotterdam, and the Netherlands Organisation for Health Research and Development. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Higher body mass index (BMI) in both partners is linked to lower fecundability and increased subfertility. Overweight and obesity in women are associated with higher odds of miscarriage.

METHODOLOGY:

• Researchers conducted a population-based prospective cohort study in Rotterdam, the Netherlands, from August 9, 2017, to July 1, 2021.
• A total of 3604 women and their partners were included, with follow-up until birth.
• BMI was measured in preconception or early pregnancy, and outcomes included fecundability, subfertility, and miscarriage.
• Fecundability was defined as the probability of conceiving within 1 month and subfertility as time to pregnancy or duration of actively pursuing pregnancy of more than 12 months or use of assisted reproductive technology.
• Miscarriage was defined as pregnancy loss before 22 weeks of gestation.

TAKEAWAY:

• Higher BMI in women and men was associated with lower fecundability: For every unit increase in BMI, fecundability decreased (women, 0.98; 95% CI, 0.97-0.99; men, 0.99; 95% CI, 0.98-1.00).
• Women with overweight (0.88; 95% CI, 0.80-0.98) and obesity (0.72; 95% CI, 0.63-0.82) had lower fecundability than women with normal weight.
• Overweight (1.35; 95% CI, 1.11-1.63) and obesity (1.67; 95% CI, 1.30-2.13) in women were associated with increased odds of subfertility.
• Obesity in men was associated with increased odds of subfertility (1.69; 95% CI, 1.24-2.31).

IN PRACTICE:

“We observed in this cohort study that BMI outside of the normal category in women and men was associated with lower fecundability, subfertility, and increased odds of miscarriage. Optimizing BMI from the preconception period onward in women and men might be an important strategy to improve fertility and pregnancy outcomes,” wrote the authors of the study.

SOURCE:

The study was led by Aline J. Boxem, MD, and Vincent W. V. Jaddoe, MD, PhD, The Generation R Study Group, Erasmus University Medical Centre in Rotterdam, the Netherlands. It was published online in JAMA Network Open.

LIMITATIONS:

The study’s generalizability may be affected by differences between included and excluded participants, who were younger and had a higher BMI. The accuracy of time-to-pregnancy duration may have been impacted by retrospectively answered questionnaires. Residual confounding might still be an issue due to the observational nature of the study.

DISCLOSURES:

Dr. Boxem and Dr. Jaddoe disclosed receiving grants from the Erasmus University Medical Centre, the Erasmus University Rotterdam, and the Netherlands Organisation for Health Research and Development. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.