Federal Practitioner

More than 10 years after the withdrawal of the weight-loss drug Mediator (benfluorex) from the market in France, the Paris Court issued its judgment on March 29, 2021, against Servier Laboratories and the French National Agency for the Safety of Medicines and Health Products (ANSM).

Servier Laboratories was convicted of “aggravated deception” and fined 2.7 million euros (approximately $3.2 million) but were found not guilty of fraud. ANSM will also have to pay a fine.

Mediator was brought to the market in 1976 for the treatment of hyperlipidemia and for overweight patients with type 2 diabetes but was used off label as an appetite suppressant. It was taken by 5 million people and was only removed from the market in France in 2009 because of its toxic effects.

Mediator was taken off the market in Spain 6 years earlier, and in Switzerland 12 years earlier, and more than 30 years before in Belgium. It was never marketed in the United States.

The number of deaths because of heart valve damage related to the drug in France has been estimated at 220-300 in the short term (2.5 years) and 1,300-1,800 in the long term. In addition, the drug has been responsible for 3,100-4,200 hospital admissions for valvular insufficiency and pulmonary arterial hypertension.

“Despite knowing the risks for very many years ... [Servier Laboratories] never took the necessary measures and thus deceived” consumers of Mediator, declared the president of the criminal court, Sylvie Daunois.

Servier has “weakened confidence in the health system,” she added.

“I am very happy that ‘aggravated deception,’ the heart of the case, has been recognized and condemned,” Irène Frachon, MD, a pulmonologist at Brest (France) University Hospital and whistleblower on the Mediator scandal, said in an interview.

However, Dr. Frachon continued: “The major problem, putting a toxic agent on the market for years, is a given. But the weakness of the sentences gives a mixed message.

“The judgment is too cautious in its punishments,” she added, pointing out that, “in the case of contaminated blood, there were prison sentences.”
 

Servier deceived doctors and patients

The French trial in September 2019 was extraordinary, with about 100 witnesses, nearly 400 lawyers, and 5,000 victims.

On June 23, 2020, the prosecutor, Aude Le Guilcher, requested at the end of her indictment that the six companies of the Servier group be fined, notably for “deception, homicide, involuntary injuries, and fraud,” to the tune of 20.3 million euros (approximately $23.8 million).

Against the former No. 2 of Servier, Jean-Philippe Seta, Ms. Le Guilcher requested 5 years in prison, with 2 years suspended, and a 200,000 euro (approximately $235,000) fine.

The same sum was requested against ANSM for homicide and unintentional injuries.

In the end, Mr. Seta, the former right hand of Jacques Servier, who died in 2004, was sentenced to 4 years in prison, suspended. For their part, ANSM was fined 303,000 euros(approximately $350,000).

It is now clearly established that Servier Laboratories knowingly concealed the similarity of Mediator to the fenfluramine family of compounds, which was banned in 1990 because of adverse effects.

The group also deceived doctors who prescribed the drug and patients who took it by hiding its toxicity.
 

Mediator should never have been authorized for use

In terms of the fraud charges, the prosecutor estimated that the losses incurred by the primary health insurance industry were in the region of several hundred million euros.

She argued that Mediator should never have been reimbursed, as “it should never have benefited from market authorization, which it received solely due to the fraudulent actions of the company.”

But because of the statute of limitations, this argument was not heard, explained Dr. Frachon, “and the same is true of conflicts of interest, where limitations led to them being discharged.

“We understand the legal difficulties, but it’s a shame in terms of the signal sent.”

“I hope the medical world will learn the lesson and not continue with ‘business as usual’ with people who are delinquents. I think it will be essential to restore public confidence,” concluded Dr. Frachon.

No conflicts of interest or funding were declared.

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

More than 10 years after the withdrawal of the weight-loss drug Mediator (benfluorex) from the market in France, the Paris Court issued its judgment on March 29, 2021, against Servier Laboratories and the French National Agency for the Safety of Medicines and Health Products (ANSM).

Servier Laboratories was convicted of “aggravated deception” and fined 2.7 million euros (approximately $3.2 million) but were found not guilty of fraud. ANSM will also have to pay a fine.

Mediator was brought to the market in 1976 for the treatment of hyperlipidemia and for overweight patients with type 2 diabetes but was used off label as an appetite suppressant. It was taken by 5 million people and was only removed from the market in France in 2009 because of its toxic effects.

Mediator was taken off the market in Spain 6 years earlier, and in Switzerland 12 years earlier, and more than 30 years before in Belgium. It was never marketed in the United States.

The number of deaths because of heart valve damage related to the drug in France has been estimated at 220-300 in the short term (2.5 years) and 1,300-1,800 in the long term. In addition, the drug has been responsible for 3,100-4,200 hospital admissions for valvular insufficiency and pulmonary arterial hypertension.

“Despite knowing the risks for very many years ... [Servier Laboratories] never took the necessary measures and thus deceived” consumers of Mediator, declared the president of the criminal court, Sylvie Daunois.

Servier has “weakened confidence in the health system,” she added.

“I am very happy that ‘aggravated deception,’ the heart of the case, has been recognized and condemned,” Irène Frachon, MD, a pulmonologist at Brest (France) University Hospital and whistleblower on the Mediator scandal, said in an interview.

However, Dr. Frachon continued: “The major problem, putting a toxic agent on the market for years, is a given. But the weakness of the sentences gives a mixed message.

“The judgment is too cautious in its punishments,” she added, pointing out that, “in the case of contaminated blood, there were prison sentences.”
 

Servier deceived doctors and patients

The French trial in September 2019 was extraordinary, with about 100 witnesses, nearly 400 lawyers, and 5,000 victims.

On June 23, 2020, the prosecutor, Aude Le Guilcher, requested at the end of her indictment that the six companies of the Servier group be fined, notably for “deception, homicide, involuntary injuries, and fraud,” to the tune of 20.3 million euros (approximately $23.8 million).

Against the former No. 2 of Servier, Jean-Philippe Seta, Ms. Le Guilcher requested 5 years in prison, with 2 years suspended, and a 200,000 euro (approximately $235,000) fine.

The same sum was requested against ANSM for homicide and unintentional injuries.

In the end, Mr. Seta, the former right hand of Jacques Servier, who died in 2004, was sentenced to 4 years in prison, suspended. For their part, ANSM was fined 303,000 euros(approximately $350,000).

It is now clearly established that Servier Laboratories knowingly concealed the similarity of Mediator to the fenfluramine family of compounds, which was banned in 1990 because of adverse effects.

The group also deceived doctors who prescribed the drug and patients who took it by hiding its toxicity.
 

Mediator should never have been authorized for use

In terms of the fraud charges, the prosecutor estimated that the losses incurred by the primary health insurance industry were in the region of several hundred million euros.

She argued that Mediator should never have been reimbursed, as “it should never have benefited from market authorization, which it received solely due to the fraudulent actions of the company.”

But because of the statute of limitations, this argument was not heard, explained Dr. Frachon, “and the same is true of conflicts of interest, where limitations led to them being discharged.

“We understand the legal difficulties, but it’s a shame in terms of the signal sent.”

“I hope the medical world will learn the lesson and not continue with ‘business as usual’ with people who are delinquents. I think it will be essential to restore public confidence,” concluded Dr. Frachon.

No conflicts of interest or funding were declared.

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

More than 10 years after the withdrawal of the weight-loss drug Mediator (benfluorex) from the market in France, the Paris Court issued its judgment on March 29, 2021, against Servier Laboratories and the French National Agency for the Safety of Medicines and Health Products (ANSM).

Servier Laboratories was convicted of “aggravated deception” and fined 2.7 million euros (approximately $3.2 million) but were found not guilty of fraud. ANSM will also have to pay a fine.

Mediator was brought to the market in 1976 for the treatment of hyperlipidemia and for overweight patients with type 2 diabetes but was used off label as an appetite suppressant. It was taken by 5 million people and was only removed from the market in France in 2009 because of its toxic effects.

Mediator was taken off the market in Spain 6 years earlier, and in Switzerland 12 years earlier, and more than 30 years before in Belgium. It was never marketed in the United States.

The number of deaths because of heart valve damage related to the drug in France has been estimated at 220-300 in the short term (2.5 years) and 1,300-1,800 in the long term. In addition, the drug has been responsible for 3,100-4,200 hospital admissions for valvular insufficiency and pulmonary arterial hypertension.

“Despite knowing the risks for very many years ... [Servier Laboratories] never took the necessary measures and thus deceived” consumers of Mediator, declared the president of the criminal court, Sylvie Daunois.

Servier has “weakened confidence in the health system,” she added.

“I am very happy that ‘aggravated deception,’ the heart of the case, has been recognized and condemned,” Irène Frachon, MD, a pulmonologist at Brest (France) University Hospital and whistleblower on the Mediator scandal, said in an interview.

However, Dr. Frachon continued: “The major problem, putting a toxic agent on the market for years, is a given. But the weakness of the sentences gives a mixed message.

“The judgment is too cautious in its punishments,” she added, pointing out that, “in the case of contaminated blood, there were prison sentences.”
 

Servier deceived doctors and patients

The French trial in September 2019 was extraordinary, with about 100 witnesses, nearly 400 lawyers, and 5,000 victims.

On June 23, 2020, the prosecutor, Aude Le Guilcher, requested at the end of her indictment that the six companies of the Servier group be fined, notably for “deception, homicide, involuntary injuries, and fraud,” to the tune of 20.3 million euros (approximately $23.8 million).

Against the former No. 2 of Servier, Jean-Philippe Seta, Ms. Le Guilcher requested 5 years in prison, with 2 years suspended, and a 200,000 euro (approximately $235,000) fine.

The same sum was requested against ANSM for homicide and unintentional injuries.

In the end, Mr. Seta, the former right hand of Jacques Servier, who died in 2004, was sentenced to 4 years in prison, suspended. For their part, ANSM was fined 303,000 euros(approximately $350,000).

It is now clearly established that Servier Laboratories knowingly concealed the similarity of Mediator to the fenfluramine family of compounds, which was banned in 1990 because of adverse effects.

The group also deceived doctors who prescribed the drug and patients who took it by hiding its toxicity.
 

Mediator should never have been authorized for use

In terms of the fraud charges, the prosecutor estimated that the losses incurred by the primary health insurance industry were in the region of several hundred million euros.

She argued that Mediator should never have been reimbursed, as “it should never have benefited from market authorization, which it received solely due to the fraudulent actions of the company.”

But because of the statute of limitations, this argument was not heard, explained Dr. Frachon, “and the same is true of conflicts of interest, where limitations led to them being discharged.

“We understand the legal difficulties, but it’s a shame in terms of the signal sent.”

“I hope the medical world will learn the lesson and not continue with ‘business as usual’ with people who are delinquents. I think it will be essential to restore public confidence,” concluded Dr. Frachon.

No conflicts of interest or funding were declared.

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

Patients at very high risk for melanoma, including those with a family history or with inherited pathogenic variants of genes that increase the risk, likely benefit from routine whole-body screening for melanoma and education about UV protection.

Those are key findings from the first prospective cohort study to quantify the benefit of screening in melanoma-prone families, which was published online April 2 in Cancer Epidemiology, Biomarkers & Prevention.

“Whole-body screening for melanoma is currently routine for individuals at high risk for melanoma, which includes people from melanoma-prone families (at least two relatives who have had melanoma) and those with inherited pathogenic gene variants of the CDKN2A or CDK4 genes, which increase risk for melanoma,” lead author Michael R. Sargen, MD, said in an interview. “In our study, we investigated whether screening and educational interventions, including education about the appearance of melanoma and strategies for protecting skin from ultraviolet damage, contributed to early diagnosis of melanoma in individuals from melanoma-prone families.”

Of the 293 individuals who enrolled in the study between 1976 and 2014, 246 were diagnosed with melanoma before enrollment (the prestudy cohort) and 47 were diagnosed after enrollment (the prospective cohort). The researchers compared differences in melanoma thickness and tumor stage between participants in the prestudy and prospective cohorts, and compared tumor-thickness trends between participants in their study and cases in the general population using data from Surveillance, Epidemiology, and End Results (SEER) registries between 1973 and 2016. Because information on melanoma thickness was missing for 24% of melanoma cases in the NCI Familial Melanoma Study and 8.7% of melanoma cases found in the SEER registry, the researchers imputed the missing data.

After adjusting for gender and age, Dr. Sargen and his colleagues found that participants in the prospective cohort had significantly thinner melanomas, compared with those in the prestudy cohort (0.6 mm vs. 1.1 mm, respectively; P < .001). In addition, 83% of those in the prospective cohort were significantly more likely to be diagnosed at the early T1 stage, compared with 40% of those in the prestudy cohort (P < .001).

In their analysis, they also determined that after adjusting for gender and age, “all NCI family cases had systematically lower thickness than SEER cases during the study period.” The reductions in melanoma thickness and tumor stage, they concluded, “were not fully explained by calendar period effects of decreasing thickness in the general population and point to the potential benefit of skin cancer screening for patients with a family history of melanoma and those with pathogenic germline variants of melanoma-susceptibility genes.”

“Our data provide reassuring evidence that screening, alongside education about proper UV protection and the appearance of melanoma, is likely benefiting patients with a significantly elevated risk for melanoma,” Dr. Sargen said in the interview “Further studies are needed to determine whether individuals without a family history of melanoma may benefit from whole-body screening, and whether the benefits vary by ethnicity.”

He acknowledged certain limitations of the study, including the relatively small sample size of melanoma cases in the NCI Familial Melanoma Study and the imputation of missing melanoma-thickness data. “Additionally, since this was a prospective cohort study, we were not able to distinguish the independent effect of each intervention,” he said. “Randomized controlled studies are needed to understand the impact of each aspect of the intervention, such as whole-body screening, melanoma education, or strategies for skin protection.”

In an interview, Maryam M. Asgari, MD, professor of dermatology at Harvard University, Boston, called the analysis “well done,” but commented on the potential role of selection bias impacting the findings. “People who have a strong family history of melanoma and who are opting to engage in an NCI study and come in for full-body skin checks and go through that education process may have very different health-seeking behaviors than individuals in the general population that would be reported to SEER,” she said.

She also raised the question of whether the results were driven by the early detection through the NCI’s program of provider screening or through the educational component that enables earlier self-detection. “If you’re an individual involved in a study and that brings attention to your moles and you have a strong family history of melanoma to begin with, it is not surprising that you are going to have heightened awareness of any changing mole and therefore are more likely to have melanoma detected at an earlier stage,” Dr. Asgari said.

The study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute. Dr. Sargen reported having no financial disclosures.
Dr. Asgari disclosed that she has received research support from the Melanoma Research Alliance.
 

[email protected]

Patients at very high risk for melanoma, including those with a family history or with inherited pathogenic variants of genes that increase the risk, likely benefit from routine whole-body screening for melanoma and education about UV protection.

Those are key findings from the first prospective cohort study to quantify the benefit of screening in melanoma-prone families, which was published online April 2 in Cancer Epidemiology, Biomarkers & Prevention.

“Whole-body screening for melanoma is currently routine for individuals at high risk for melanoma, which includes people from melanoma-prone families (at least two relatives who have had melanoma) and those with inherited pathogenic gene variants of the CDKN2A or CDK4 genes, which increase risk for melanoma,” lead author Michael R. Sargen, MD, said in an interview. “In our study, we investigated whether screening and educational interventions, including education about the appearance of melanoma and strategies for protecting skin from ultraviolet damage, contributed to early diagnosis of melanoma in individuals from melanoma-prone families.”

Of the 293 individuals who enrolled in the study between 1976 and 2014, 246 were diagnosed with melanoma before enrollment (the prestudy cohort) and 47 were diagnosed after enrollment (the prospective cohort). The researchers compared differences in melanoma thickness and tumor stage between participants in the prestudy and prospective cohorts, and compared tumor-thickness trends between participants in their study and cases in the general population using data from Surveillance, Epidemiology, and End Results (SEER) registries between 1973 and 2016. Because information on melanoma thickness was missing for 24% of melanoma cases in the NCI Familial Melanoma Study and 8.7% of melanoma cases found in the SEER registry, the researchers imputed the missing data.

After adjusting for gender and age, Dr. Sargen and his colleagues found that participants in the prospective cohort had significantly thinner melanomas, compared with those in the prestudy cohort (0.6 mm vs. 1.1 mm, respectively; P < .001). In addition, 83% of those in the prospective cohort were significantly more likely to be diagnosed at the early T1 stage, compared with 40% of those in the prestudy cohort (P < .001).

In their analysis, they also determined that after adjusting for gender and age, “all NCI family cases had systematically lower thickness than SEER cases during the study period.” The reductions in melanoma thickness and tumor stage, they concluded, “were not fully explained by calendar period effects of decreasing thickness in the general population and point to the potential benefit of skin cancer screening for patients with a family history of melanoma and those with pathogenic germline variants of melanoma-susceptibility genes.”

“Our data provide reassuring evidence that screening, alongside education about proper UV protection and the appearance of melanoma, is likely benefiting patients with a significantly elevated risk for melanoma,” Dr. Sargen said in the interview “Further studies are needed to determine whether individuals without a family history of melanoma may benefit from whole-body screening, and whether the benefits vary by ethnicity.”

He acknowledged certain limitations of the study, including the relatively small sample size of melanoma cases in the NCI Familial Melanoma Study and the imputation of missing melanoma-thickness data. “Additionally, since this was a prospective cohort study, we were not able to distinguish the independent effect of each intervention,” he said. “Randomized controlled studies are needed to understand the impact of each aspect of the intervention, such as whole-body screening, melanoma education, or strategies for skin protection.”

In an interview, Maryam M. Asgari, MD, professor of dermatology at Harvard University, Boston, called the analysis “well done,” but commented on the potential role of selection bias impacting the findings. “People who have a strong family history of melanoma and who are opting to engage in an NCI study and come in for full-body skin checks and go through that education process may have very different health-seeking behaviors than individuals in the general population that would be reported to SEER,” she said.

She also raised the question of whether the results were driven by the early detection through the NCI’s program of provider screening or through the educational component that enables earlier self-detection. “If you’re an individual involved in a study and that brings attention to your moles and you have a strong family history of melanoma to begin with, it is not surprising that you are going to have heightened awareness of any changing mole and therefore are more likely to have melanoma detected at an earlier stage,” Dr. Asgari said.

The study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute. Dr. Sargen reported having no financial disclosures.
Dr. Asgari disclosed that she has received research support from the Melanoma Research Alliance.
 

[email protected]

Patients at very high risk for melanoma, including those with a family history or with inherited pathogenic variants of genes that increase the risk, likely benefit from routine whole-body screening for melanoma and education about UV protection.

Those are key findings from the first prospective cohort study to quantify the benefit of screening in melanoma-prone families, which was published online April 2 in Cancer Epidemiology, Biomarkers & Prevention.

“Whole-body screening for melanoma is currently routine for individuals at high risk for melanoma, which includes people from melanoma-prone families (at least two relatives who have had melanoma) and those with inherited pathogenic gene variants of the CDKN2A or CDK4 genes, which increase risk for melanoma,” lead author Michael R. Sargen, MD, said in an interview. “In our study, we investigated whether screening and educational interventions, including education about the appearance of melanoma and strategies for protecting skin from ultraviolet damage, contributed to early diagnosis of melanoma in individuals from melanoma-prone families.”

Of the 293 individuals who enrolled in the study between 1976 and 2014, 246 were diagnosed with melanoma before enrollment (the prestudy cohort) and 47 were diagnosed after enrollment (the prospective cohort). The researchers compared differences in melanoma thickness and tumor stage between participants in the prestudy and prospective cohorts, and compared tumor-thickness trends between participants in their study and cases in the general population using data from Surveillance, Epidemiology, and End Results (SEER) registries between 1973 and 2016. Because information on melanoma thickness was missing for 24% of melanoma cases in the NCI Familial Melanoma Study and 8.7% of melanoma cases found in the SEER registry, the researchers imputed the missing data.

After adjusting for gender and age, Dr. Sargen and his colleagues found that participants in the prospective cohort had significantly thinner melanomas, compared with those in the prestudy cohort (0.6 mm vs. 1.1 mm, respectively; P < .001). In addition, 83% of those in the prospective cohort were significantly more likely to be diagnosed at the early T1 stage, compared with 40% of those in the prestudy cohort (P < .001).

In their analysis, they also determined that after adjusting for gender and age, “all NCI family cases had systematically lower thickness than SEER cases during the study period.” The reductions in melanoma thickness and tumor stage, they concluded, “were not fully explained by calendar period effects of decreasing thickness in the general population and point to the potential benefit of skin cancer screening for patients with a family history of melanoma and those with pathogenic germline variants of melanoma-susceptibility genes.”

“Our data provide reassuring evidence that screening, alongside education about proper UV protection and the appearance of melanoma, is likely benefiting patients with a significantly elevated risk for melanoma,” Dr. Sargen said in the interview “Further studies are needed to determine whether individuals without a family history of melanoma may benefit from whole-body screening, and whether the benefits vary by ethnicity.”

He acknowledged certain limitations of the study, including the relatively small sample size of melanoma cases in the NCI Familial Melanoma Study and the imputation of missing melanoma-thickness data. “Additionally, since this was a prospective cohort study, we were not able to distinguish the independent effect of each intervention,” he said. “Randomized controlled studies are needed to understand the impact of each aspect of the intervention, such as whole-body screening, melanoma education, or strategies for skin protection.”

In an interview, Maryam M. Asgari, MD, professor of dermatology at Harvard University, Boston, called the analysis “well done,” but commented on the potential role of selection bias impacting the findings. “People who have a strong family history of melanoma and who are opting to engage in an NCI study and come in for full-body skin checks and go through that education process may have very different health-seeking behaviors than individuals in the general population that would be reported to SEER,” she said.

She also raised the question of whether the results were driven by the early detection through the NCI’s program of provider screening or through the educational component that enables earlier self-detection. “If you’re an individual involved in a study and that brings attention to your moles and you have a strong family history of melanoma to begin with, it is not surprising that you are going to have heightened awareness of any changing mole and therefore are more likely to have melanoma detected at an earlier stage,” Dr. Asgari said.

The study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute. Dr. Sargen reported having no financial disclosures.
Dr. Asgari disclosed that she has received research support from the Melanoma Research Alliance.
 

[email protected]

April 5 is the official start date of a U.S. law requiring health care organizations to provide patients with free, full, and immediate electronic access to their doctor’s clinical notes as well as test results and reports from pathology and imaging.

The mandate, called “open notes” by many, is part of the 21st Century Cures Act, a wide-ranging piece of federal health care legislation. The previous deadline of Nov. 2, 2020, for enacting open notes was extended last year because of the exigencies of the COVID-19 pandemic.

Organizations must provide access via patient portals to the following types of notes: consultations, discharge summaries, histories, physical examination findings, imaging narratives, laboratory and pathology report narratives, and procedure and progress notes. Noncompliant organizations will eventually be subject to fines from the Department of Health & Human Services for “information blocking.”

This news organization reported on the mandate in 2020, and some readers said it was an unwelcome intrusion into practice. Since then, this news organization has run additional open notes stories about physician concerns, a perspective essay addressing those fears, and a reader poll about the phenomenon.

Now, as the legislation turns into a practical clinical matter, there are five key points clinicians should consider.
 

Clinicians don’t have to change writing style.

The new law mandates timely patient access to notes and test results, but it doesn’t require that clinicians alter their writing, said Scott MacDonald, MD, an internist and electronic health record medical director at University of California Davis Health in Sacramento.

“You don’t have to change your notes,” he said. However, patients are now part of the note audience and some health care systems are directing clinicians to make patient-friendly style changes.

Everyday experience should guide clinicians when writing notes, said one expert.

“When you’re not sure [of how to write a note], just mirror the way you would speak in the office – that’s going to get you right, including for mental health issues,” advised Leonor Fernandez, MD, an internist at Beth Deaconess Israel Medical Center, Boston, in her “take-away” comments in the online video, How to Write an Open Note.

According to a 2020 Medscape poll of 1,050 physicians, a majority (56%) anticipate that they will write notes differently, knowing that patients can read them via open notes. Nearly two-thirds (64%) believe that this new wrinkle in medical records will increase their workload. However, actual practice suggests that this is true for a minority of practitioners, according to the results from a recent study of more than 1,000 physicians in Boston, Seattle, and rural Pennsylvania, who already work in open notes settings. Only about one-third (37%) reported “spending more time on documentation.”

Note writing is going to change because of the addition of the patient reader, and something will be lost, argued Steven Reidbord, MD, a psychiatrist in private practice in San Francisco. By watering down the language for patients, “you are trading away the technical precision and other advantages of having a professional language,” commented Dr. Reidbord, who blogs for Psychology Today and has criticized the open notes movement in the past.

However, years of investigation from OpenNotes, the Boston-based advocacy and research organization, indicates that there are many gains with patient-accessible notes, including improved medical record accuracy, greater medication adherence, and potentially improved health care disparities among a range of patient types. In a 2019 study, researchers said that worry and confusion among note-reading patients are uncommon (5% and 3%, respectively), which addresses two criticisms voiced by multiple people last year.
 

Some clinical notes can be withheld. 

The new rules from the federal government permit information blocking if there is clear evidence that doing so “will substantially reduce the risk of harm” to patients or to other third parties, Tom Delbanco, MD, and Charlotte Blease, PhD, of OpenNotes in Boston wrote in a commentary in February 2021.

There are also state-level laws that can supersede the new U.S. law and block access to notes, points out MacDonald. For example, California law dictates that providers cannot post cancer test results without talking with the patient first.

The OpenNotes organization also points out that, with regard to sensitive psychotherapy notes that are separated from the rest of a medical record, those notes “can be kept from patients without their permission, and such rules vary state by state.”
 

Some patients are more likely readers. 

Some patients are more likely to peer into their files than others, said Liz Salmi, senior strategist at OpenNotes, who is also a brain cancer patient.

“Those patients who have more serious or chronic conditions ... are more likely to read their notes,” she said in an interview.

A new study of nearly 6,000 medical oncology patients at the University of Wisconsin confirmed that opinion. Patients with incurable metastatic disease were much more likely than those with early-stage, curable disease to read notes. Notably, younger patients were more likely than older ones to access notes, likely the result of generational tech savvy.

Despite the unpredictability of serious disease such as cancer, oncology patients find satisfaction in reading their notes, say experts. “We’ve overwhelmingly heard that patients like it,” Thomas LeBlanc, MD, medical oncologist at Duke University, Durham, N.C., where all patients already have access to clinicians’ notes, told this news organization in 2018.
 

You are part of the avant garde. 

The United States and Scandinavian countries are the world leaders in implementing open notes in clinical practice, Dr. Blease said in an interview.

“It’s a phenomenal achievement” to have enacted open notes nationally, she said. For example, there are no open notes in Northern Ireland, Dr. Blease’s home country, or most of Europe.

In the United States, there are more than 200 medical organizations, including at least one in every state, that were voluntarily providing open notes before April 5, including interstate giants such as Banner Health and big-name medical centers such as Cleveland Clinic.

It may be hard for the United States to top Sweden’s embrace of the practice. The national open notes program now has 7.2 million patient accounts in a country of 10 million people, noted Maria Häggland, PhD, of Uppsala (Sweden) MedTech Science Innovation Center during a webinar last year.
 

The start day will come, and you may not notice. 

“When April 5 happens, something brand new is going to happen symbolically,” Ms. Salmi said. Its importance is hard to measure.

“Patients say they trust their doctor more because they understand their thinking with open notes. How do you value that? We don’t have metrics for that,” she said.

Dr. MacDonald suggested that open notes are both new and not new. In the fall of 2020, he predicted that the launch day would come, and few clinicians would notice, in part because many patients already access truncated information via patient portals.

However, there are “sensitive issues,” such as with adolescents and reproductive health, where “we know that some parents have sign-in information for their teen’s portal,” he commented. With clinical notes now on full display, potential problems “may be out of our control.”

Still, the Sacramento-based physician and IT officer acknowledged that concerns about open notes may be a bit inflated. “I’ve been more worried about reassuring physicians that everything will be okay than what’s actually going to happen [as the law takes effect],” Dr. MacDonald said.

The OpenNotes organization is grant funded, and staff disclosed no relevant financial relationships.

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

April 5 is the official start date of a U.S. law requiring health care organizations to provide patients with free, full, and immediate electronic access to their doctor’s clinical notes as well as test results and reports from pathology and imaging.

The mandate, called “open notes” by many, is part of the 21st Century Cures Act, a wide-ranging piece of federal health care legislation. The previous deadline of Nov. 2, 2020, for enacting open notes was extended last year because of the exigencies of the COVID-19 pandemic.

Organizations must provide access via patient portals to the following types of notes: consultations, discharge summaries, histories, physical examination findings, imaging narratives, laboratory and pathology report narratives, and procedure and progress notes. Noncompliant organizations will eventually be subject to fines from the Department of Health & Human Services for “information blocking.”

This news organization reported on the mandate in 2020, and some readers said it was an unwelcome intrusion into practice. Since then, this news organization has run additional open notes stories about physician concerns, a perspective essay addressing those fears, and a reader poll about the phenomenon.

Now, as the legislation turns into a practical clinical matter, there are five key points clinicians should consider.
 

Clinicians don’t have to change writing style.

The new law mandates timely patient access to notes and test results, but it doesn’t require that clinicians alter their writing, said Scott MacDonald, MD, an internist and electronic health record medical director at University of California Davis Health in Sacramento.

“You don’t have to change your notes,” he said. However, patients are now part of the note audience and some health care systems are directing clinicians to make patient-friendly style changes.

Everyday experience should guide clinicians when writing notes, said one expert.

“When you’re not sure [of how to write a note], just mirror the way you would speak in the office – that’s going to get you right, including for mental health issues,” advised Leonor Fernandez, MD, an internist at Beth Deaconess Israel Medical Center, Boston, in her “take-away” comments in the online video, How to Write an Open Note.

According to a 2020 Medscape poll of 1,050 physicians, a majority (56%) anticipate that they will write notes differently, knowing that patients can read them via open notes. Nearly two-thirds (64%) believe that this new wrinkle in medical records will increase their workload. However, actual practice suggests that this is true for a minority of practitioners, according to the results from a recent study of more than 1,000 physicians in Boston, Seattle, and rural Pennsylvania, who already work in open notes settings. Only about one-third (37%) reported “spending more time on documentation.”

Note writing is going to change because of the addition of the patient reader, and something will be lost, argued Steven Reidbord, MD, a psychiatrist in private practice in San Francisco. By watering down the language for patients, “you are trading away the technical precision and other advantages of having a professional language,” commented Dr. Reidbord, who blogs for Psychology Today and has criticized the open notes movement in the past.

However, years of investigation from OpenNotes, the Boston-based advocacy and research organization, indicates that there are many gains with patient-accessible notes, including improved medical record accuracy, greater medication adherence, and potentially improved health care disparities among a range of patient types. In a 2019 study, researchers said that worry and confusion among note-reading patients are uncommon (5% and 3%, respectively), which addresses two criticisms voiced by multiple people last year.
 

Some clinical notes can be withheld. 

The new rules from the federal government permit information blocking if there is clear evidence that doing so “will substantially reduce the risk of harm” to patients or to other third parties, Tom Delbanco, MD, and Charlotte Blease, PhD, of OpenNotes in Boston wrote in a commentary in February 2021.

There are also state-level laws that can supersede the new U.S. law and block access to notes, points out MacDonald. For example, California law dictates that providers cannot post cancer test results without talking with the patient first.

The OpenNotes organization also points out that, with regard to sensitive psychotherapy notes that are separated from the rest of a medical record, those notes “can be kept from patients without their permission, and such rules vary state by state.”
 

Some patients are more likely readers. 

Some patients are more likely to peer into their files than others, said Liz Salmi, senior strategist at OpenNotes, who is also a brain cancer patient.

“Those patients who have more serious or chronic conditions ... are more likely to read their notes,” she said in an interview.

A new study of nearly 6,000 medical oncology patients at the University of Wisconsin confirmed that opinion. Patients with incurable metastatic disease were much more likely than those with early-stage, curable disease to read notes. Notably, younger patients were more likely than older ones to access notes, likely the result of generational tech savvy.

Despite the unpredictability of serious disease such as cancer, oncology patients find satisfaction in reading their notes, say experts. “We’ve overwhelmingly heard that patients like it,” Thomas LeBlanc, MD, medical oncologist at Duke University, Durham, N.C., where all patients already have access to clinicians’ notes, told this news organization in 2018.
 

You are part of the avant garde. 

The United States and Scandinavian countries are the world leaders in implementing open notes in clinical practice, Dr. Blease said in an interview.

“It’s a phenomenal achievement” to have enacted open notes nationally, she said. For example, there are no open notes in Northern Ireland, Dr. Blease’s home country, or most of Europe.

In the United States, there are more than 200 medical organizations, including at least one in every state, that were voluntarily providing open notes before April 5, including interstate giants such as Banner Health and big-name medical centers such as Cleveland Clinic.

It may be hard for the United States to top Sweden’s embrace of the practice. The national open notes program now has 7.2 million patient accounts in a country of 10 million people, noted Maria Häggland, PhD, of Uppsala (Sweden) MedTech Science Innovation Center during a webinar last year.
 

The start day will come, and you may not notice. 

“When April 5 happens, something brand new is going to happen symbolically,” Ms. Salmi said. Its importance is hard to measure.

“Patients say they trust their doctor more because they understand their thinking with open notes. How do you value that? We don’t have metrics for that,” she said.

Dr. MacDonald suggested that open notes are both new and not new. In the fall of 2020, he predicted that the launch day would come, and few clinicians would notice, in part because many patients already access truncated information via patient portals.

However, there are “sensitive issues,” such as with adolescents and reproductive health, where “we know that some parents have sign-in information for their teen’s portal,” he commented. With clinical notes now on full display, potential problems “may be out of our control.”

Still, the Sacramento-based physician and IT officer acknowledged that concerns about open notes may be a bit inflated. “I’ve been more worried about reassuring physicians that everything will be okay than what’s actually going to happen [as the law takes effect],” Dr. MacDonald said.

The OpenNotes organization is grant funded, and staff disclosed no relevant financial relationships.

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

April 5 is the official start date of a U.S. law requiring health care organizations to provide patients with free, full, and immediate electronic access to their doctor’s clinical notes as well as test results and reports from pathology and imaging.

The mandate, called “open notes” by many, is part of the 21st Century Cures Act, a wide-ranging piece of federal health care legislation. The previous deadline of Nov. 2, 2020, for enacting open notes was extended last year because of the exigencies of the COVID-19 pandemic.

Organizations must provide access via patient portals to the following types of notes: consultations, discharge summaries, histories, physical examination findings, imaging narratives, laboratory and pathology report narratives, and procedure and progress notes. Noncompliant organizations will eventually be subject to fines from the Department of Health & Human Services for “information blocking.”

This news organization reported on the mandate in 2020, and some readers said it was an unwelcome intrusion into practice. Since then, this news organization has run additional open notes stories about physician concerns, a perspective essay addressing those fears, and a reader poll about the phenomenon.

Now, as the legislation turns into a practical clinical matter, there are five key points clinicians should consider.
 

Clinicians don’t have to change writing style.

The new law mandates timely patient access to notes and test results, but it doesn’t require that clinicians alter their writing, said Scott MacDonald, MD, an internist and electronic health record medical director at University of California Davis Health in Sacramento.

“You don’t have to change your notes,” he said. However, patients are now part of the note audience and some health care systems are directing clinicians to make patient-friendly style changes.

Everyday experience should guide clinicians when writing notes, said one expert.

“When you’re not sure [of how to write a note], just mirror the way you would speak in the office – that’s going to get you right, including for mental health issues,” advised Leonor Fernandez, MD, an internist at Beth Deaconess Israel Medical Center, Boston, in her “take-away” comments in the online video, How to Write an Open Note.

According to a 2020 Medscape poll of 1,050 physicians, a majority (56%) anticipate that they will write notes differently, knowing that patients can read them via open notes. Nearly two-thirds (64%) believe that this new wrinkle in medical records will increase their workload. However, actual practice suggests that this is true for a minority of practitioners, according to the results from a recent study of more than 1,000 physicians in Boston, Seattle, and rural Pennsylvania, who already work in open notes settings. Only about one-third (37%) reported “spending more time on documentation.”

Note writing is going to change because of the addition of the patient reader, and something will be lost, argued Steven Reidbord, MD, a psychiatrist in private practice in San Francisco. By watering down the language for patients, “you are trading away the technical precision and other advantages of having a professional language,” commented Dr. Reidbord, who blogs for Psychology Today and has criticized the open notes movement in the past.

However, years of investigation from OpenNotes, the Boston-based advocacy and research organization, indicates that there are many gains with patient-accessible notes, including improved medical record accuracy, greater medication adherence, and potentially improved health care disparities among a range of patient types. In a 2019 study, researchers said that worry and confusion among note-reading patients are uncommon (5% and 3%, respectively), which addresses two criticisms voiced by multiple people last year.
 

Some clinical notes can be withheld. 

The new rules from the federal government permit information blocking if there is clear evidence that doing so “will substantially reduce the risk of harm” to patients or to other third parties, Tom Delbanco, MD, and Charlotte Blease, PhD, of OpenNotes in Boston wrote in a commentary in February 2021.

There are also state-level laws that can supersede the new U.S. law and block access to notes, points out MacDonald. For example, California law dictates that providers cannot post cancer test results without talking with the patient first.

The OpenNotes organization also points out that, with regard to sensitive psychotherapy notes that are separated from the rest of a medical record, those notes “can be kept from patients without their permission, and such rules vary state by state.”
 

Some patients are more likely readers. 

Some patients are more likely to peer into their files than others, said Liz Salmi, senior strategist at OpenNotes, who is also a brain cancer patient.

“Those patients who have more serious or chronic conditions ... are more likely to read their notes,” she said in an interview.

A new study of nearly 6,000 medical oncology patients at the University of Wisconsin confirmed that opinion. Patients with incurable metastatic disease were much more likely than those with early-stage, curable disease to read notes. Notably, younger patients were more likely than older ones to access notes, likely the result of generational tech savvy.

Despite the unpredictability of serious disease such as cancer, oncology patients find satisfaction in reading their notes, say experts. “We’ve overwhelmingly heard that patients like it,” Thomas LeBlanc, MD, medical oncologist at Duke University, Durham, N.C., where all patients already have access to clinicians’ notes, told this news organization in 2018.
 

You are part of the avant garde. 

The United States and Scandinavian countries are the world leaders in implementing open notes in clinical practice, Dr. Blease said in an interview.

“It’s a phenomenal achievement” to have enacted open notes nationally, she said. For example, there are no open notes in Northern Ireland, Dr. Blease’s home country, or most of Europe.

In the United States, there are more than 200 medical organizations, including at least one in every state, that were voluntarily providing open notes before April 5, including interstate giants such as Banner Health and big-name medical centers such as Cleveland Clinic.

It may be hard for the United States to top Sweden’s embrace of the practice. The national open notes program now has 7.2 million patient accounts in a country of 10 million people, noted Maria Häggland, PhD, of Uppsala (Sweden) MedTech Science Innovation Center during a webinar last year.
 

The start day will come, and you may not notice. 

“When April 5 happens, something brand new is going to happen symbolically,” Ms. Salmi said. Its importance is hard to measure.

“Patients say they trust their doctor more because they understand their thinking with open notes. How do you value that? We don’t have metrics for that,” she said.

Dr. MacDonald suggested that open notes are both new and not new. In the fall of 2020, he predicted that the launch day would come, and few clinicians would notice, in part because many patients already access truncated information via patient portals.

However, there are “sensitive issues,” such as with adolescents and reproductive health, where “we know that some parents have sign-in information for their teen’s portal,” he commented. With clinical notes now on full display, potential problems “may be out of our control.”

Still, the Sacramento-based physician and IT officer acknowledged that concerns about open notes may be a bit inflated. “I’ve been more worried about reassuring physicians that everything will be okay than what’s actually going to happen [as the law takes effect],” Dr. MacDonald said.

The OpenNotes organization is grant funded, and staff disclosed no relevant financial relationships.

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

COVID-19 was the third-leading cause of death in the United States in 2020, but that mortality burden did not fall evenly along racial/ethnic lines, according to a provisional report from the Centers for Disease Control and Prevention.

Only heart disease and cancer caused more deaths than SARS-CoV-2, which took the lives of almost 378,000 Americans last year, Farida B. Ahmad, MPH, and associates at the National Center for Health Statistics noted March 31 in the Morbidity and Mortality Weekly Report.

That represents 11.2% of the almost 3.36 million total deaths recorded in 2020. The racial/ethnics demographics, however, show that 22.4% of all deaths among Hispanic Americans were COVID-19–related, as were 18.6% of deaths in American Indians/Alaska Natives. Deaths among Asian persons, at 14.7%, and African Americans, at 13.5%, were closer but still above the national figure, while Whites (9.3%) were the only major subgroup below it, based on data from the National Vital Statistics System.

Age-adjusted death rates tell a somewhat different story: American Indian/Alaska native persons were highest with a rate of 187.8 COVID-19–associated deaths per 100,000 standard population, with Hispanic persons second at 164.3 per 100,000. Blacks were next at 151.1 deaths per 100,000, but Whites had a higher rate (72.5) than did Asian Americans (66.7), the CDC investigators reported.

“During January-December 2020, the estimated 2020 age-adjusted death rate increased for the first time since 2017, with an increase of 15.9% compared with 2019, from 715.2 to 828.7 deaths per 100,000 population,” they wrote, noting that “certain categories of race (i.e., AI/AN and Asian) and Hispanic ethnicity reported on death certificates might have been misclassified, possibly resulting in underestimates of death rates for some groups.”

[email protected]

COVID-19 was the third-leading cause of death in the United States in 2020, but that mortality burden did not fall evenly along racial/ethnic lines, according to a provisional report from the Centers for Disease Control and Prevention.

Only heart disease and cancer caused more deaths than SARS-CoV-2, which took the lives of almost 378,000 Americans last year, Farida B. Ahmad, MPH, and associates at the National Center for Health Statistics noted March 31 in the Morbidity and Mortality Weekly Report.

That represents 11.2% of the almost 3.36 million total deaths recorded in 2020. The racial/ethnics demographics, however, show that 22.4% of all deaths among Hispanic Americans were COVID-19–related, as were 18.6% of deaths in American Indians/Alaska Natives. Deaths among Asian persons, at 14.7%, and African Americans, at 13.5%, were closer but still above the national figure, while Whites (9.3%) were the only major subgroup below it, based on data from the National Vital Statistics System.

Age-adjusted death rates tell a somewhat different story: American Indian/Alaska native persons were highest with a rate of 187.8 COVID-19–associated deaths per 100,000 standard population, with Hispanic persons second at 164.3 per 100,000. Blacks were next at 151.1 deaths per 100,000, but Whites had a higher rate (72.5) than did Asian Americans (66.7), the CDC investigators reported.

“During January-December 2020, the estimated 2020 age-adjusted death rate increased for the first time since 2017, with an increase of 15.9% compared with 2019, from 715.2 to 828.7 deaths per 100,000 population,” they wrote, noting that “certain categories of race (i.e., AI/AN and Asian) and Hispanic ethnicity reported on death certificates might have been misclassified, possibly resulting in underestimates of death rates for some groups.”

[email protected]

COVID-19 was the third-leading cause of death in the United States in 2020, but that mortality burden did not fall evenly along racial/ethnic lines, according to a provisional report from the Centers for Disease Control and Prevention.

Only heart disease and cancer caused more deaths than SARS-CoV-2, which took the lives of almost 378,000 Americans last year, Farida B. Ahmad, MPH, and associates at the National Center for Health Statistics noted March 31 in the Morbidity and Mortality Weekly Report.

That represents 11.2% of the almost 3.36 million total deaths recorded in 2020. The racial/ethnics demographics, however, show that 22.4% of all deaths among Hispanic Americans were COVID-19–related, as were 18.6% of deaths in American Indians/Alaska Natives. Deaths among Asian persons, at 14.7%, and African Americans, at 13.5%, were closer but still above the national figure, while Whites (9.3%) were the only major subgroup below it, based on data from the National Vital Statistics System.

Age-adjusted death rates tell a somewhat different story: American Indian/Alaska native persons were highest with a rate of 187.8 COVID-19–associated deaths per 100,000 standard population, with Hispanic persons second at 164.3 per 100,000. Blacks were next at 151.1 deaths per 100,000, but Whites had a higher rate (72.5) than did Asian Americans (66.7), the CDC investigators reported.

“During January-December 2020, the estimated 2020 age-adjusted death rate increased for the first time since 2017, with an increase of 15.9% compared with 2019, from 715.2 to 828.7 deaths per 100,000 population,” they wrote, noting that “certain categories of race (i.e., AI/AN and Asian) and Hispanic ethnicity reported on death certificates might have been misclassified, possibly resulting in underestimates of death rates for some groups.”

[email protected]

Judicious organ matching for older liver transplant candidates with hepatocellular carcinoma (HCC) leads to survival outcomes similar to those in younger recipients, a case review suggests.

Overall survival (OS) rates among transplant recipients included in a prospective institutional database were 85.5% and 84% at 3 years after liver transplant in patients aged 65 years and under and those over 65 years, respectively. The 5-year survival rates were 73.9% and 77%, respectively (P = .26), Ola Ahmed, MD, of the department of abdominal organ transplantation surgery at Washington University, St. Louis, and colleagues found.

The investigators looked at 1,629 patients diagnosed with HCC between Jan. 1, 2002, and Dec. 31, 2019 of whom 700 were considered for curative surgery, including transplant in 538, and resection in 162.

The patients had a mean age of 62.8 years. Those older than 65 years were less likely to be considered or listed for transplant (27% vs. 73%, P < .01), although oncologic staging and delisting rates were similar in both groups. “This observation still holds true after controlling for other variables, including viral hepatitis and gender in the multivariable analysis (adjusted odds ratio, 0.365),” the investigators reported in the Journal of the American College of Surgeons.

The findings were also reported at the 2020 virtual Western Surgical Association 128th Scientific Session in November.
 

The issue of resection

Surgical intervention occurred in 597 patients, including 392 and 205 aged 65 years and younger and over 65 years, respectively.

OS was lower among patients who underwent resection, compared with the liver transplant recipients, but was similar in the older and younger age groups (3-year OS, 59% vs. 64.8% and 5-year OS, 44.8% vs. 49%; P = .13). No differences were noted in the development of local or distant metastatic disease after transplant or resection.

The two age groups had comparable ICU stays (2 days) and total hospital length of stay (6 days). There were no differences in 30- and 90-day hospital readmissions, they noted.

“On additional age analysis, 65% of transplanted patients over 65 years are currently alive and were disease free at the end of the study period, compared to only 18% of their resected counterparts (P < .01),” they wrote.

Justifying transplant

The findings are notable because despite the effectiveness of transplant as an alternative treatment for unresectable HCC, older patients are often excluded from consideration for transplant. Most studies over the past 15 years have focused on patients aged under 60 years and the ability to extrapolate results to older patients has been limited. Further, results have been conflicting in older patients, the authors explained.

“This is particularly apposite at this time with prolonged life expectancy and the growing interest in improving cancer survivorship,” they noted, adding that “there is logic in challenging existing gold standards and traditional norms with real-life medical practice.

Indeed, the current findings suggest – perhaps contrary to common perceptions – that transplant in carefully selected patients “can be justified in older age groups and provide clinically meaningful and longer survival benefits,” they said, adding that “discussions should be guided by the potential for unfair age discriminations and precise terminology of physiologic rather than actual age.

“Such insights highlight the continued need for quality improvement in the surgical management of older patients, raising questions regarding current resource utilization among different age groups and how age can influence patterns of cancer care,” they concluded.

The authors reported having no disclosures.

[email protected]

Judicious organ matching for older liver transplant candidates with hepatocellular carcinoma (HCC) leads to survival outcomes similar to those in younger recipients, a case review suggests.

Overall survival (OS) rates among transplant recipients included in a prospective institutional database were 85.5% and 84% at 3 years after liver transplant in patients aged 65 years and under and those over 65 years, respectively. The 5-year survival rates were 73.9% and 77%, respectively (P = .26), Ola Ahmed, MD, of the department of abdominal organ transplantation surgery at Washington University, St. Louis, and colleagues found.

The investigators looked at 1,629 patients diagnosed with HCC between Jan. 1, 2002, and Dec. 31, 2019 of whom 700 were considered for curative surgery, including transplant in 538, and resection in 162.

The patients had a mean age of 62.8 years. Those older than 65 years were less likely to be considered or listed for transplant (27% vs. 73%, P < .01), although oncologic staging and delisting rates were similar in both groups. “This observation still holds true after controlling for other variables, including viral hepatitis and gender in the multivariable analysis (adjusted odds ratio, 0.365),” the investigators reported in the Journal of the American College of Surgeons.

The findings were also reported at the 2020 virtual Western Surgical Association 128th Scientific Session in November.
 

The issue of resection

Surgical intervention occurred in 597 patients, including 392 and 205 aged 65 years and younger and over 65 years, respectively.

OS was lower among patients who underwent resection, compared with the liver transplant recipients, but was similar in the older and younger age groups (3-year OS, 59% vs. 64.8% and 5-year OS, 44.8% vs. 49%; P = .13). No differences were noted in the development of local or distant metastatic disease after transplant or resection.

The two age groups had comparable ICU stays (2 days) and total hospital length of stay (6 days). There were no differences in 30- and 90-day hospital readmissions, they noted.

“On additional age analysis, 65% of transplanted patients over 65 years are currently alive and were disease free at the end of the study period, compared to only 18% of their resected counterparts (P < .01),” they wrote.

Justifying transplant

The findings are notable because despite the effectiveness of transplant as an alternative treatment for unresectable HCC, older patients are often excluded from consideration for transplant. Most studies over the past 15 years have focused on patients aged under 60 years and the ability to extrapolate results to older patients has been limited. Further, results have been conflicting in older patients, the authors explained.

“This is particularly apposite at this time with prolonged life expectancy and the growing interest in improving cancer survivorship,” they noted, adding that “there is logic in challenging existing gold standards and traditional norms with real-life medical practice.

Indeed, the current findings suggest – perhaps contrary to common perceptions – that transplant in carefully selected patients “can be justified in older age groups and provide clinically meaningful and longer survival benefits,” they said, adding that “discussions should be guided by the potential for unfair age discriminations and precise terminology of physiologic rather than actual age.

“Such insights highlight the continued need for quality improvement in the surgical management of older patients, raising questions regarding current resource utilization among different age groups and how age can influence patterns of cancer care,” they concluded.

The authors reported having no disclosures.

[email protected]

Judicious organ matching for older liver transplant candidates with hepatocellular carcinoma (HCC) leads to survival outcomes similar to those in younger recipients, a case review suggests.

Overall survival (OS) rates among transplant recipients included in a prospective institutional database were 85.5% and 84% at 3 years after liver transplant in patients aged 65 years and under and those over 65 years, respectively. The 5-year survival rates were 73.9% and 77%, respectively (P = .26), Ola Ahmed, MD, of the department of abdominal organ transplantation surgery at Washington University, St. Louis, and colleagues found.

The investigators looked at 1,629 patients diagnosed with HCC between Jan. 1, 2002, and Dec. 31, 2019 of whom 700 were considered for curative surgery, including transplant in 538, and resection in 162.

The patients had a mean age of 62.8 years. Those older than 65 years were less likely to be considered or listed for transplant (27% vs. 73%, P < .01), although oncologic staging and delisting rates were similar in both groups. “This observation still holds true after controlling for other variables, including viral hepatitis and gender in the multivariable analysis (adjusted odds ratio, 0.365),” the investigators reported in the Journal of the American College of Surgeons.

The findings were also reported at the 2020 virtual Western Surgical Association 128th Scientific Session in November.
 

The issue of resection

Surgical intervention occurred in 597 patients, including 392 and 205 aged 65 years and younger and over 65 years, respectively.

OS was lower among patients who underwent resection, compared with the liver transplant recipients, but was similar in the older and younger age groups (3-year OS, 59% vs. 64.8% and 5-year OS, 44.8% vs. 49%; P = .13). No differences were noted in the development of local or distant metastatic disease after transplant or resection.

The two age groups had comparable ICU stays (2 days) and total hospital length of stay (6 days). There were no differences in 30- and 90-day hospital readmissions, they noted.

“On additional age analysis, 65% of transplanted patients over 65 years are currently alive and were disease free at the end of the study period, compared to only 18% of their resected counterparts (P < .01),” they wrote.

Justifying transplant

The findings are notable because despite the effectiveness of transplant as an alternative treatment for unresectable HCC, older patients are often excluded from consideration for transplant. Most studies over the past 15 years have focused on patients aged under 60 years and the ability to extrapolate results to older patients has been limited. Further, results have been conflicting in older patients, the authors explained.

“This is particularly apposite at this time with prolonged life expectancy and the growing interest in improving cancer survivorship,” they noted, adding that “there is logic in challenging existing gold standards and traditional norms with real-life medical practice.

Indeed, the current findings suggest – perhaps contrary to common perceptions – that transplant in carefully selected patients “can be justified in older age groups and provide clinically meaningful and longer survival benefits,” they said, adding that “discussions should be guided by the potential for unfair age discriminations and precise terminology of physiologic rather than actual age.

“Such insights highlight the continued need for quality improvement in the surgical management of older patients, raising questions regarding current resource utilization among different age groups and how age can influence patterns of cancer care,” they concluded.

The authors reported having no disclosures.

[email protected]

For select older patients, it is safe to switch to a lower dose of lenalidomide maintenance therapy and discontinue dexamethasone after 9 months. The regimen is safe and yields outcomes similar to those of standard, continuous lenalidomide/dexamethasone (Rd), according to new findings.

At a median follow-up of 37 months, event-free survival was 10.4 months in the experimental arm in which dexamethasone therapy was stopped (Rd-R) versus 6.9 months for standard therapy. The tailored approach also resulted in fewer adverse effects.

The authors noted that there was no difference in progression-free survival (PFS) and overall survival between the two groups.

“These results may be useful for the treatment of myeloma patients, since approximately one-third of patients not eligible for stem cell transplantation are intermediate fit, the population in our study,” said lead author Alessandra Larocca, MD, PhD, from the department of hematology-oncology of the University Hospital Città della Salute e della Scienza, Torino, Italy.

She said in an interview that they expect that these findings “may help to optimize the treatment of less-fit elderly patients by reducing the occurrence of adverse events and thus improving outcomes and preserving quality of life of these patients.”

This approach is a viable option for clinicians to consider for some patient subgroups. “This steroid-sparing approach can also be used in other combinations,” she said. “Ongoing trials are now evaluating steroid sparing in combination with monoclonal antibodies or the role of frailty-guided treatment.”

The study was published March 19, 2021, in Blood.
 

Curtailing steroids

Myeloma patients aged 75 years or older or who have comorbidities and functional impairments are an understudied population. They are more susceptible to adverse events that may negatively affect the duration of treatment and outcomes. Steroids are “scarcely tolerated” in the long term, even among younger patients, and “whether sparing dexamethasone is as effective as prolonged steroid exposure remains an open issue,” the authors wrote. There are still no clear data on the advantage of continuous steroid treatment as opposed to fixed-duration treatment for newly diagnosed patients.

In 2010, a study compared high-dose with low-dose dexamethasone. As expected, the rate of adverse events was lower among patients who received the low-dose steroid, but quite unexpectedly, deaths with high-dose dexamethasone were significantly higher than with low-dose dexamethasone.

The 1-year overall survival was 96% among patients who received the low dose of dexamethasone versus 87% with the standard high dose.

S. Vincent Rajkumar, MD, of the Mayo Clinic, Rochester, Minn., who was the lead author of the 2010 study, spoke with this new organization about the current study. “This is an important and practice-changing study,” he said. “We have already changed our practice and recommendations based on this study.”

He explained that, for transplant-ineligible patients, instead of initial therapy with bortezomib-lenalidomide-dexamethasone followed by Rd, they use lenalidomide alone without steroids.

“After 9 months of initial therapy, I now recommend we stop dexamethasone unless we are having problems controlling the myeloma, such as progressive disease,” Dr. Rajkumar said. “I congratulate the authors on a study that will improve the quality of life for our patients.”
 

Improved event-free survival

In this study, Dr. Larocca and colleagues investigated the efficacy and feasibility of a dose- and schedule-adjusted Rd regimen that was followed by maintenance Rd-R 10 mg/d and compared the regimen with continuous Rd in elderly, intermediate-fit patients who were newly diagnosed with multiple myeloma.

The primary endpoint was event-free survival, defined as progression/death from any cause, lenalidomide discontinuation, and any hematologic grade 4 or nonhematologic grade 3-4 adverse events.

The cohort consisted of 199 patients who were randomly assigned to receive either Rd-R (n = 101) or continuous Rd (n = 98). The median age was 75 years in the Rd-R arm and 76 years in the Rd arm; 52% of patients in the Rd-R group and 43% in the Rd group were classified as being intermediate fit not for age but for geriatric impairments.

With a median follow-up of 37 months, event-free survival was 10.4 months in the Rd-R arm versus 6.9 months in the Rd arm (hazard ratio, 0.70; P = .02). This benefit was maintained beyond nine cycles (median: 19.8 vs. 10.6 months for Rd-R vs. Rd; HR, 0.55; P = .03)

The median PFS was 20.2 months with Rd-R and 18.3 months with Rd (HR, 0.78; P = .16). The median overall survival was not reached. The 3-year overall survival was 74% with Rd-R and 63% with continuous Rd (HR, 0.62; P = .06). Among patients remaining on therapy after nine cycles, no difference in median PFS was observed between the two groups (24.3 vs. 18.7 months; HR, 0.73; P = .19).

Best response was similar for both groups, with an overall response rate of 78% versus 68% (P = .15). The very good partial response rate was 51% in the Rd-R arm versus 39% in the continuous Rd arm (P = .09).

Toxicities were similar between the two groups. Hematologic adverse events of at least grade 3 were reported in 26% of Rd-R patients versus 20% of Rd patients (P = .40). In both groups, the most frequent grade ≥3 hematologic toxicity was neutropenia (21% vs 18%). The most frequent grade ≥3 toxicities were nonhematologic. They occurred in 33% of Rd-R patients and 43% of Rd patients (P = .15). The most frequent nonhematologic toxicities were infections (10% vs. 12%), constitutional (3% vs. 12%), dermatologic (7% vs. 3%), and central nervous toxicities (2% vs. 6%).

The study was sponsored by Fondazione EMN Italy Onlus. Dr. Larocca has received honoraria from Amgen, Bristol-Myers Squibb, Celgene, Janssen, and GlaxoSmithKline, and has served on the advisory boards for Bristol-Myers Squibb, Celgene, Janssen, and Takeda. Several coauthors also have disclosed relationships with industry. Dr. Rajkumar disclosed no relevant financial relationships.

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

For select older patients, it is safe to switch to a lower dose of lenalidomide maintenance therapy and discontinue dexamethasone after 9 months. The regimen is safe and yields outcomes similar to those of standard, continuous lenalidomide/dexamethasone (Rd), according to new findings.

At a median follow-up of 37 months, event-free survival was 10.4 months in the experimental arm in which dexamethasone therapy was stopped (Rd-R) versus 6.9 months for standard therapy. The tailored approach also resulted in fewer adverse effects.

The authors noted that there was no difference in progression-free survival (PFS) and overall survival between the two groups.

“These results may be useful for the treatment of myeloma patients, since approximately one-third of patients not eligible for stem cell transplantation are intermediate fit, the population in our study,” said lead author Alessandra Larocca, MD, PhD, from the department of hematology-oncology of the University Hospital Città della Salute e della Scienza, Torino, Italy.

She said in an interview that they expect that these findings “may help to optimize the treatment of less-fit elderly patients by reducing the occurrence of adverse events and thus improving outcomes and preserving quality of life of these patients.”

This approach is a viable option for clinicians to consider for some patient subgroups. “This steroid-sparing approach can also be used in other combinations,” she said. “Ongoing trials are now evaluating steroid sparing in combination with monoclonal antibodies or the role of frailty-guided treatment.”

The study was published March 19, 2021, in Blood.
 

Curtailing steroids

Myeloma patients aged 75 years or older or who have comorbidities and functional impairments are an understudied population. They are more susceptible to adverse events that may negatively affect the duration of treatment and outcomes. Steroids are “scarcely tolerated” in the long term, even among younger patients, and “whether sparing dexamethasone is as effective as prolonged steroid exposure remains an open issue,” the authors wrote. There are still no clear data on the advantage of continuous steroid treatment as opposed to fixed-duration treatment for newly diagnosed patients.

In 2010, a study compared high-dose with low-dose dexamethasone. As expected, the rate of adverse events was lower among patients who received the low-dose steroid, but quite unexpectedly, deaths with high-dose dexamethasone were significantly higher than with low-dose dexamethasone.

The 1-year overall survival was 96% among patients who received the low dose of dexamethasone versus 87% with the standard high dose.

S. Vincent Rajkumar, MD, of the Mayo Clinic, Rochester, Minn., who was the lead author of the 2010 study, spoke with this new organization about the current study. “This is an important and practice-changing study,” he said. “We have already changed our practice and recommendations based on this study.”

He explained that, for transplant-ineligible patients, instead of initial therapy with bortezomib-lenalidomide-dexamethasone followed by Rd, they use lenalidomide alone without steroids.

“After 9 months of initial therapy, I now recommend we stop dexamethasone unless we are having problems controlling the myeloma, such as progressive disease,” Dr. Rajkumar said. “I congratulate the authors on a study that will improve the quality of life for our patients.”
 

Improved event-free survival

In this study, Dr. Larocca and colleagues investigated the efficacy and feasibility of a dose- and schedule-adjusted Rd regimen that was followed by maintenance Rd-R 10 mg/d and compared the regimen with continuous Rd in elderly, intermediate-fit patients who were newly diagnosed with multiple myeloma.

The primary endpoint was event-free survival, defined as progression/death from any cause, lenalidomide discontinuation, and any hematologic grade 4 or nonhematologic grade 3-4 adverse events.

The cohort consisted of 199 patients who were randomly assigned to receive either Rd-R (n = 101) or continuous Rd (n = 98). The median age was 75 years in the Rd-R arm and 76 years in the Rd arm; 52% of patients in the Rd-R group and 43% in the Rd group were classified as being intermediate fit not for age but for geriatric impairments.

With a median follow-up of 37 months, event-free survival was 10.4 months in the Rd-R arm versus 6.9 months in the Rd arm (hazard ratio, 0.70; P = .02). This benefit was maintained beyond nine cycles (median: 19.8 vs. 10.6 months for Rd-R vs. Rd; HR, 0.55; P = .03)

The median PFS was 20.2 months with Rd-R and 18.3 months with Rd (HR, 0.78; P = .16). The median overall survival was not reached. The 3-year overall survival was 74% with Rd-R and 63% with continuous Rd (HR, 0.62; P = .06). Among patients remaining on therapy after nine cycles, no difference in median PFS was observed between the two groups (24.3 vs. 18.7 months; HR, 0.73; P = .19).

Best response was similar for both groups, with an overall response rate of 78% versus 68% (P = .15). The very good partial response rate was 51% in the Rd-R arm versus 39% in the continuous Rd arm (P = .09).

Toxicities were similar between the two groups. Hematologic adverse events of at least grade 3 were reported in 26% of Rd-R patients versus 20% of Rd patients (P = .40). In both groups, the most frequent grade ≥3 hematologic toxicity was neutropenia (21% vs 18%). The most frequent grade ≥3 toxicities were nonhematologic. They occurred in 33% of Rd-R patients and 43% of Rd patients (P = .15). The most frequent nonhematologic toxicities were infections (10% vs. 12%), constitutional (3% vs. 12%), dermatologic (7% vs. 3%), and central nervous toxicities (2% vs. 6%).

The study was sponsored by Fondazione EMN Italy Onlus. Dr. Larocca has received honoraria from Amgen, Bristol-Myers Squibb, Celgene, Janssen, and GlaxoSmithKline, and has served on the advisory boards for Bristol-Myers Squibb, Celgene, Janssen, and Takeda. Several coauthors also have disclosed relationships with industry. Dr. Rajkumar disclosed no relevant financial relationships.

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

For select older patients, it is safe to switch to a lower dose of lenalidomide maintenance therapy and discontinue dexamethasone after 9 months. The regimen is safe and yields outcomes similar to those of standard, continuous lenalidomide/dexamethasone (Rd), according to new findings.

At a median follow-up of 37 months, event-free survival was 10.4 months in the experimental arm in which dexamethasone therapy was stopped (Rd-R) versus 6.9 months for standard therapy. The tailored approach also resulted in fewer adverse effects.

The authors noted that there was no difference in progression-free survival (PFS) and overall survival between the two groups.

“These results may be useful for the treatment of myeloma patients, since approximately one-third of patients not eligible for stem cell transplantation are intermediate fit, the population in our study,” said lead author Alessandra Larocca, MD, PhD, from the department of hematology-oncology of the University Hospital Città della Salute e della Scienza, Torino, Italy.

She said in an interview that they expect that these findings “may help to optimize the treatment of less-fit elderly patients by reducing the occurrence of adverse events and thus improving outcomes and preserving quality of life of these patients.”

This approach is a viable option for clinicians to consider for some patient subgroups. “This steroid-sparing approach can also be used in other combinations,” she said. “Ongoing trials are now evaluating steroid sparing in combination with monoclonal antibodies or the role of frailty-guided treatment.”

The study was published March 19, 2021, in Blood.
 

Curtailing steroids

Myeloma patients aged 75 years or older or who have comorbidities and functional impairments are an understudied population. They are more susceptible to adverse events that may negatively affect the duration of treatment and outcomes. Steroids are “scarcely tolerated” in the long term, even among younger patients, and “whether sparing dexamethasone is as effective as prolonged steroid exposure remains an open issue,” the authors wrote. There are still no clear data on the advantage of continuous steroid treatment as opposed to fixed-duration treatment for newly diagnosed patients.

In 2010, a study compared high-dose with low-dose dexamethasone. As expected, the rate of adverse events was lower among patients who received the low-dose steroid, but quite unexpectedly, deaths with high-dose dexamethasone were significantly higher than with low-dose dexamethasone.

The 1-year overall survival was 96% among patients who received the low dose of dexamethasone versus 87% with the standard high dose.

S. Vincent Rajkumar, MD, of the Mayo Clinic, Rochester, Minn., who was the lead author of the 2010 study, spoke with this new organization about the current study. “This is an important and practice-changing study,” he said. “We have already changed our practice and recommendations based on this study.”

He explained that, for transplant-ineligible patients, instead of initial therapy with bortezomib-lenalidomide-dexamethasone followed by Rd, they use lenalidomide alone without steroids.

“After 9 months of initial therapy, I now recommend we stop dexamethasone unless we are having problems controlling the myeloma, such as progressive disease,” Dr. Rajkumar said. “I congratulate the authors on a study that will improve the quality of life for our patients.”
 

Improved event-free survival

In this study, Dr. Larocca and colleagues investigated the efficacy and feasibility of a dose- and schedule-adjusted Rd regimen that was followed by maintenance Rd-R 10 mg/d and compared the regimen with continuous Rd in elderly, intermediate-fit patients who were newly diagnosed with multiple myeloma.

The primary endpoint was event-free survival, defined as progression/death from any cause, lenalidomide discontinuation, and any hematologic grade 4 or nonhematologic grade 3-4 adverse events.

The cohort consisted of 199 patients who were randomly assigned to receive either Rd-R (n = 101) or continuous Rd (n = 98). The median age was 75 years in the Rd-R arm and 76 years in the Rd arm; 52% of patients in the Rd-R group and 43% in the Rd group were classified as being intermediate fit not for age but for geriatric impairments.

With a median follow-up of 37 months, event-free survival was 10.4 months in the Rd-R arm versus 6.9 months in the Rd arm (hazard ratio, 0.70; P = .02). This benefit was maintained beyond nine cycles (median: 19.8 vs. 10.6 months for Rd-R vs. Rd; HR, 0.55; P = .03)

The median PFS was 20.2 months with Rd-R and 18.3 months with Rd (HR, 0.78; P = .16). The median overall survival was not reached. The 3-year overall survival was 74% with Rd-R and 63% with continuous Rd (HR, 0.62; P = .06). Among patients remaining on therapy after nine cycles, no difference in median PFS was observed between the two groups (24.3 vs. 18.7 months; HR, 0.73; P = .19).

Best response was similar for both groups, with an overall response rate of 78% versus 68% (P = .15). The very good partial response rate was 51% in the Rd-R arm versus 39% in the continuous Rd arm (P = .09).

Toxicities were similar between the two groups. Hematologic adverse events of at least grade 3 were reported in 26% of Rd-R patients versus 20% of Rd patients (P = .40). In both groups, the most frequent grade ≥3 hematologic toxicity was neutropenia (21% vs 18%). The most frequent grade ≥3 toxicities were nonhematologic. They occurred in 33% of Rd-R patients and 43% of Rd patients (P = .15). The most frequent nonhematologic toxicities were infections (10% vs. 12%), constitutional (3% vs. 12%), dermatologic (7% vs. 3%), and central nervous toxicities (2% vs. 6%).

The study was sponsored by Fondazione EMN Italy Onlus. Dr. Larocca has received honoraria from Amgen, Bristol-Myers Squibb, Celgene, Janssen, and GlaxoSmithKline, and has served on the advisory boards for Bristol-Myers Squibb, Celgene, Janssen, and Takeda. Several coauthors also have disclosed relationships with industry. Dr. Rajkumar disclosed no relevant financial relationships.

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

More adolescent girls than boys experienced nonfatal opioid overdose and reported baseline levels of anxiety, depression, and self-harm, according to data from a retrospective cohort study of more than 20,000 youth in the United States.

Previous studies have identified sex-based differences in opioid overdose such as a higher prevalence of co-occurring psychiatric disorders in women compared with men, wrote Sarah M. Bagley, MD, of Boston University, and colleagues. “However, few studies have examined whether such sex-based differences in opioid overdose risk extend to the population of adolescents and young adults,” they said.

In a retrospective cohort study published in JAMA Network Open, the researchers identified 20,312 commercially insured youth aged 11-24 years who experienced a nonfatal opioid overdose between Jan. 1, 2006, and Dec. 31, 2017, and reviewed data using the IBM MarketScan Commercial Database. The average age of the study population was 20 years and approximately 42% were female.

Females aged 11-16 years had a significantly higher incidence of nonfatal opioid overdose (60%) compared with males, but this trend reversed at age 17 years, after which the incidence of nonfatal opioid overdose became significantly higher in males. “Our finding that females younger than 17 years had a higher incidence of NFOD is consistent with epidemiologic data that have indicated changes in alcohol and drug prevalence among female youths,” the researchers wrote.

Overall, 57.8% of the cohort had mood and anxiety disorders, 12.8% had trauma- or stress-related disorders, and 11.7% had attention-deficit/hyperactivity disorder.

When analyzed by sex, females had a significantly higher prevalence than that of males of mood or anxiety disorders (65.5% vs. 51.9%) trauma or stress-related disorders (16.4% vs. 10.1%) and attempts at suicide or self-harm (14.6% vs. 9.9%). Males had significantly higher prevalence than that of females of opioid use disorder (44.7% vs. 29.2%), cannabis use disorder (18.3% vs. 11.3%), and alcohol use disorder (20.3% vs. 14.4%).

“Although in our study, female youths had a lower prevalence of all substance use disorders, including OUD [opioid use disorder], and a higher prevalence of mood and trauma-associated disorders, both male and female youths had a higher prevalence of psychiatric illness and substance use disorder than youths in the general population,” the researchers noted.

The study findings were limited by several factors including the inclusion only of youth with commercial insurance, with no uninsured or publicly insured youth, and only those youth who sought health care after a nonfatal opioid overdose, the researchers noted. The prevalence of substance use and mental health disorders may be over- or underdiagnosed, and race was not included as a variable because of unreliable data, they added. The database also did not allow for gender identity beyond sex as listed by the insurance carrier, they said.

However, the results indicate significant differences in the incidence of nonfatal opioid overdose and accompanying mental health and substance use disorders based on age and sex, they said.

“These differences may have important implications for developing effective interventions to prevent first-time NFOD and to engage youths in care after an NFOD,” they concluded.

The study was supported by grants to several researchers from the National Institute on Drug Abuse, National Institutes of Health, and the Charles A. King Trust. The researchers had no financial conflicts to disclose. 

More adolescent girls than boys experienced nonfatal opioid overdose and reported baseline levels of anxiety, depression, and self-harm, according to data from a retrospective cohort study of more than 20,000 youth in the United States.

Previous studies have identified sex-based differences in opioid overdose such as a higher prevalence of co-occurring psychiatric disorders in women compared with men, wrote Sarah M. Bagley, MD, of Boston University, and colleagues. “However, few studies have examined whether such sex-based differences in opioid overdose risk extend to the population of adolescents and young adults,” they said.

In a retrospective cohort study published in JAMA Network Open, the researchers identified 20,312 commercially insured youth aged 11-24 years who experienced a nonfatal opioid overdose between Jan. 1, 2006, and Dec. 31, 2017, and reviewed data using the IBM MarketScan Commercial Database. The average age of the study population was 20 years and approximately 42% were female.

Females aged 11-16 years had a significantly higher incidence of nonfatal opioid overdose (60%) compared with males, but this trend reversed at age 17 years, after which the incidence of nonfatal opioid overdose became significantly higher in males. “Our finding that females younger than 17 years had a higher incidence of NFOD is consistent with epidemiologic data that have indicated changes in alcohol and drug prevalence among female youths,” the researchers wrote.

Overall, 57.8% of the cohort had mood and anxiety disorders, 12.8% had trauma- or stress-related disorders, and 11.7% had attention-deficit/hyperactivity disorder.

When analyzed by sex, females had a significantly higher prevalence than that of males of mood or anxiety disorders (65.5% vs. 51.9%) trauma or stress-related disorders (16.4% vs. 10.1%) and attempts at suicide or self-harm (14.6% vs. 9.9%). Males had significantly higher prevalence than that of females of opioid use disorder (44.7% vs. 29.2%), cannabis use disorder (18.3% vs. 11.3%), and alcohol use disorder (20.3% vs. 14.4%).

“Although in our study, female youths had a lower prevalence of all substance use disorders, including OUD [opioid use disorder], and a higher prevalence of mood and trauma-associated disorders, both male and female youths had a higher prevalence of psychiatric illness and substance use disorder than youths in the general population,” the researchers noted.

The study findings were limited by several factors including the inclusion only of youth with commercial insurance, with no uninsured or publicly insured youth, and only those youth who sought health care after a nonfatal opioid overdose, the researchers noted. The prevalence of substance use and mental health disorders may be over- or underdiagnosed, and race was not included as a variable because of unreliable data, they added. The database also did not allow for gender identity beyond sex as listed by the insurance carrier, they said.

However, the results indicate significant differences in the incidence of nonfatal opioid overdose and accompanying mental health and substance use disorders based on age and sex, they said.

“These differences may have important implications for developing effective interventions to prevent first-time NFOD and to engage youths in care after an NFOD,” they concluded.

The study was supported by grants to several researchers from the National Institute on Drug Abuse, National Institutes of Health, and the Charles A. King Trust. The researchers had no financial conflicts to disclose. 

More adolescent girls than boys experienced nonfatal opioid overdose and reported baseline levels of anxiety, depression, and self-harm, according to data from a retrospective cohort study of more than 20,000 youth in the United States.

Previous studies have identified sex-based differences in opioid overdose such as a higher prevalence of co-occurring psychiatric disorders in women compared with men, wrote Sarah M. Bagley, MD, of Boston University, and colleagues. “However, few studies have examined whether such sex-based differences in opioid overdose risk extend to the population of adolescents and young adults,” they said.

In a retrospective cohort study published in JAMA Network Open, the researchers identified 20,312 commercially insured youth aged 11-24 years who experienced a nonfatal opioid overdose between Jan. 1, 2006, and Dec. 31, 2017, and reviewed data using the IBM MarketScan Commercial Database. The average age of the study population was 20 years and approximately 42% were female.

Females aged 11-16 years had a significantly higher incidence of nonfatal opioid overdose (60%) compared with males, but this trend reversed at age 17 years, after which the incidence of nonfatal opioid overdose became significantly higher in males. “Our finding that females younger than 17 years had a higher incidence of NFOD is consistent with epidemiologic data that have indicated changes in alcohol and drug prevalence among female youths,” the researchers wrote.

Overall, 57.8% of the cohort had mood and anxiety disorders, 12.8% had trauma- or stress-related disorders, and 11.7% had attention-deficit/hyperactivity disorder.

When analyzed by sex, females had a significantly higher prevalence than that of males of mood or anxiety disorders (65.5% vs. 51.9%) trauma or stress-related disorders (16.4% vs. 10.1%) and attempts at suicide or self-harm (14.6% vs. 9.9%). Males had significantly higher prevalence than that of females of opioid use disorder (44.7% vs. 29.2%), cannabis use disorder (18.3% vs. 11.3%), and alcohol use disorder (20.3% vs. 14.4%).

“Although in our study, female youths had a lower prevalence of all substance use disorders, including OUD [opioid use disorder], and a higher prevalence of mood and trauma-associated disorders, both male and female youths had a higher prevalence of psychiatric illness and substance use disorder than youths in the general population,” the researchers noted.

The study findings were limited by several factors including the inclusion only of youth with commercial insurance, with no uninsured or publicly insured youth, and only those youth who sought health care after a nonfatal opioid overdose, the researchers noted. The prevalence of substance use and mental health disorders may be over- or underdiagnosed, and race was not included as a variable because of unreliable data, they added. The database also did not allow for gender identity beyond sex as listed by the insurance carrier, they said.

However, the results indicate significant differences in the incidence of nonfatal opioid overdose and accompanying mental health and substance use disorders based on age and sex, they said.

“These differences may have important implications for developing effective interventions to prevent first-time NFOD and to engage youths in care after an NFOD,” they concluded.

The study was supported by grants to several researchers from the National Institute on Drug Abuse, National Institutes of Health, and the Charles A. King Trust. The researchers had no financial conflicts to disclose. 

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system, with recent estimates of around 1 million people living with MS in the US.¹ In many countries, MS is a leading cause of disability among young adults, second only to trauma.² Clinically, neurologic worsening (ie, disability) in MS can occur in the relapsing-remitting (RRMS) phase of disease due to incomplete recovery from neuroinflammatory relapses. However, in the 15% of patients with a progressive course from onset (PPMS), and in those with RRMS who transition to a secondary progressive phenotype (SPMS), neurologic worsening follows a slowly progressive pattern.³ A progressive disease course—either PPMS at onset or transitioning to SPMS—is the dominant factor affecting MS-related neurologic disability accumulation. In particular, epidemiologic studies have shown that, in the absence of transitioning to a progressive disease course, < 5% of individuals with MS will accumulate sufficient disability to necessitate use of a cane for ambulation.^4-6 Therefore, developing disease modifying therapies (DMTs) that are highly effective at slowing or stopping the gradual accumulation of neurologic disability in progressive MS represent a critical unmet need.

Research into the development of DMTs for progressive MS has been hindered by a number of factors. In particular, the clinical definition and diagnosis of progressive MS has been an evolving concept. Diagnostic criteria for MS, which help facilitate the enrollment of appropriate subjects into clinical trials, have only recently clarified the current consensus definition for progressive MS—steadily increasing neurologic disability independent of clinical relapses. Looking back to the Schumacher criteria in 1965 and Poser criteria in 1983, it was acknowledged that neurologic symptoms in MS may follow a relapsing-remitting or progressive pattern, but little attempt was made to define progressive MS.^7,8 The original McDonald criteria in 2001 defined diagnostic criteria for progressive MS.⁹ These criteria continued to evolve through subsequent revisions (eg, cerebrospinal fluid [CSF] specific oligoclonal bands no longer are an absolute requirement), and only in the 2017 revision was it emphasized that disability progression must occur independent of clinical relapses, concordant with similar emphasis in the 2013 revision of MS clinical course definitions.^3,10

The interpretation of prior clinical trials of DMT for progressive MS must consider this evolving clinical definition. The US Food and Drug Administration (FDA) approved mitoxantrone in 2000—making it the first DMT to carry an approved label for SPMS. While achieving significant clinical efficacy, it is clear from the details of the trial that the enrolled subjects had a high degree of inflammatory disease activity, which suggests that mitoxantrone treats neuroinflammation and not relapse-independent worsening. More recently, disparate results were seen in the anti-CD20 (rituximab, ocrelizumab) and S1P receptor modulator (fingolimod, siponimod) trials targeted at patients with primary and secondary progressive MS.^11-14 Although there are differences between these therapies, they are more similar than not within the same therapeutic class. Taken together, these trials illustrate the critical impact the narrower inclusion/exclusion criteria (namely age and extent of inflammatory activity) had on attaining positive outcomes. Other considerations, such as confounding illness, also may impact trial recruitment and generalizability of findings.

The lack of known biological targets in progressive MS, which is a complex disease with an incompletely understood and heterogeneous pathology, also hinders DMT development. Decades of research has characterized multifocal central nervous system (CNS) lesions that exhibit features of demyelination, inflammation, reactive gliosis, axonal loss, and neuronal damage. Until recently, however, much of this research focused on the relapsing phase of disease, and so the understanding of the pathologic underpinnings of progressive disease has remained limited. Current areas of investigation encompass a broad range of pathological processes, such as microglial activation, meningeal lymphoid follicles, remyelination failure, vulnerability of chronically demyelinated axons, oxidative injury, iron accumulation, mitochondrial damage, and others. There is the added complication that the pathologic processes underlying progressive MS are superimposed on the CNS aging process. In particular, the transition to progressive MS and the rate of disability accumulation during progressive MS show strong correlation with age.^6,15-17

Finally, DMT development for progressive MS also is hindered by the lack of specific surrogate and clinical outcome measures. Trials for relapsing MS have benefited greatly from the relatively straightforward assessment of clinical relapses and inflammatory disease activity on magnetic resonance imaging (MRI). With the goal of developing DMTs that are highly effective at slowing or stopping the gradual accumulation of neurologic disability in progressive MS, which by definition occurs independent of clinical relapses, these measures are not directly relevant. The longitudinal clinical disability outcome measures change at a slower rate than in early, relapsing disease. The use of standardized scales (eg, the Expanded Disability Status Scale [EDSS]), lower limb function, upper limb function, cognition, or a combination is a subject of ongoing debate. For example, the ASCEND and IMPACT trials (placebo-controlled trials for SPMS with natalizumab and interferon β-1a, respectively) showed no significant impact in EDSS progression—but in both of these trials, the 9-hole peg test (9-HPT), a performance measure for upper limb function, showed significant improvement.^10,18 Particularly in those with an EDSS of > 6.5, who are unlikely to have measurable EDSS progression, functional tests such as the 9-HPT or timed 25-foot walk may be more sensitive as measures for disability progression.¹¹ MRI measures of brain atrophy is the current gold standard surrogate outcome for clinical trials in progressive MS, but others that may warrant consideration include optical coherence tomography (OCT) or CSF markers of axonal degeneration.

DMT for Progressive MS

Current diagnostic nomenclature separates patients with active (superimposed clinical and/or radiographic relapses) from those with inactive disease.^3,12 Relapsing forms of MS include all RRMS and those with SPMS with superimposed relapses (ie, active SPMS). Following this paradigm shift, the FDA changed the indication for already approved DMT from RRMS to relapsing forms of MS. Below is a discussion of DMT that specifically use the term SPMS and PPMS in the indication, where phase 3 trial data for progressive MS is available.

In 2019, the FDA approved the first oral medication (siponimod) for active SPMS. Subsequently, updates to the labels of the older DMT expanded to include active SPMS. Until 2019, the only FDA approved medication for SPMS was mitoxantrone, and use of this medication was limited due to unfavorable adverse effects (AEs). No medications had obtained FDA approval for inactive SPMS to this point, which represented an unmet need for a considerable number of patients.

Mitoxantrone became the first DMT approved for use in SPMS in 2000 following early trials that showed reductions in EDSS worsening, change in ambulation index, reduced number of treated relapses, and prolonged time to first treated relapse. However, as with some of the other positive trials in progressive MS, it is difficult to discern the impact of suppression of relapses as opposed to direct impact on progressive pathophysiology. Within the placebo arm, for example, there were 129 relapses among the 64 subjects, which suggests that these cases had particularly active disease or were in the early stages of SPMS.¹³ Furthermore, the use of this medication was limited due to concerns of cardiotoxicity and hematologic malignancy as serious AEs.

The trials of interferon β-1b illustrate the same difficulty of isolating possible benefits in disease progression from disability accumulated from relapses. The first interferon β-1b trial for SPMS, was conducted in Europe using fingolimod and showed a delay in confirmed disability progression compared to placebo as measured with the EDSS.¹⁴ However, a North American trial that followed in 2004 was unable to replicate this finding.¹⁵ The patients in the European trial appeared to be in an earlier phase of SPMS with more active disease, and a post-hoc pooled analysis suggested that patients with active disease and those with more pronounced disability progression were more likely to benefit from treatment.¹⁶ Overall, interferons do not appear to appreciably alter disability in the long-term for patients with SPMS, though they may modify short-term, relapse-related disability.

Perhaps the most encouraging data for SPMS was found in the EXPAND trial, which investigated siponimod, an S1P receptor modulator that is more selective than fingolimod. The trial identified a 21% reduction in 3-month confirmed disability progression for SPMS patients taking siponimod compared with those taking a placebo.¹⁷ Although the patients in EXPAND did seem to have relatively less disease activity at baseline than those who participated in other SPMS trials, those who benefitted from siponimod were primarily patients who had clinical and/or radiographic relapses over the prior 2 years. Based on this, the FDA approved siponimod for active SPMS. The extent to which siponimod exerts a true neuroprotective effect beyond reducing inflammation has not been clearly established.

B-cell depleting therapies rituximab and ocrelizumab have been evaluated in both primary and secondary progressive MS populations. Early investigations of the chimeric rituximab in PPMS did not show benefits on disability (EDSS) progression; however, benefits were seen in analysis of some subgroups.¹⁸ With this in mind, the ORATORIO trial for the humanized version, ocreluzimab, included PPMS patients that were younger (aged < 55 years) and had cutoffs for disease duration (< 15 years for those with EDSS more than 5 years, < 10 years for those with EDSS less than 5 years). The study showed statistically significant changes on disability progression, which led to ocrelizumab receiving the first FDA indication for PPMS.¹¹ There are substantial pathophysiologic similarities between PPMS and SPMS in the progressive phase.¹⁹ While these medications may have similar effects across these disease processes, these benefits have not yet been demonstrated in a prospective trial for the SPMS population. Regardless, B-cell depleting therapy is a reasonable consideration for select patients with active SPMS, consistent with a relapsing form of MS.

Therapies in Development 

DMT development for progressive MS is a high priority area. Current immunomodulatory therapies for RRMS have consistently been ineffective in the inactive forms of MS, with the possible exceptions of ocrelizumab and siponimod. Therefore, instead of immunosuppression, many agents currently in phase 2 and 3 clinical trials target alternative pathophysiological processes in order to provide neuroprotection, and/or promote remyelination and neurogenesis. These targets include oxidative stress (OS), non-T cell mediated inflammation, and mitochondrial/energy failure.²⁰ Below we review a selection of clinical trials testing agents following these approaches. Many agents have more than one potential mechanism of action (MOA) that could benefit progressive MS.

Lipoic acid (LA), also known as α-lipoic acid and thiotic acid, is one such agent targeting alternative pathophysiology in SPMS. LA is an endogenous agent synthesized de novo from fatty acids and cysteine as well as obtained in small amounts from foods.²¹ It has antioxidant (AO) properties including direct radical scavenging, regeneration of glutathione, and upregulation of AO enzymes via the NrF2 pathway.²² It supports mitochondria as a key cofactor for pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, and it also aids mitochondrial DNA synthesis.^21,22 Studies in experimental autoimmune encephalomyelitis, a widely used experimental mouse model of inflammatory demyelinating disease, also indicate a reduction in excessive microglial activation.²³ A phase 2 pilot randomized controlled trial (RCT) of 1200 mg LA in SPMS (n = 51) resulted in significantly less whole brain atrophy by SIENA (Structural Image Evaluation, Using Normalization, of Atrophy) at 2 years.²⁴ A follow-up multicenter trial is ongoing.

Simvastatin also targets alternative pathophysiology in SPMS. It has anti-inflammatory effects, improves vascular function, and promotes neuroprotection by reducing excitotoxicity. A phase 2 RCT demonstrated a reduction in whole brain atrophy in SPMS (n = 140), and a phase 3 trial is underway.²⁵ Ibudilast is another repurposed drug that targets alternative inflammation by inhibiting several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor and toll-like receptor 4. A phase 2 trial (n = 225) in both SPMS and PPMS also demonstrated a reduction in brain atrophy, but participants had high rates of AEs.²⁶

Lithium and riluzole promote neuroprotection by reducing excitotoxicity. Lithium is a pharmacologic active cation used as a mood stabilizer and causes inhibition of glycogen synthase kinase-3β. Animal models also indicate that lithium may decrease inflammation and positively impact neurogenesis.²⁷ A crossover pilot trial demonstrated tolerability with trends toward stabilization of EDSS and reductions in brain atrophy.²⁸ Three neuroprotective agents, riluzole (reduces glutamate excitotoxicity), fluoxetine (stimulates glycogenolysis and improves mitochondrial energy production), and amiloride (an acid-sensing ion channel blocker that opens in response to inflammation) were tested in a phase 2b multi-arm, multi-site parallel group RCT in SPMS (n = 445). The study failed to yield differences from placebo for any agent in reduction of brain volume loss.²⁹ A prior study of lamotrigine, a sodium channel blocker, also failed to find changes in brain volume loss.³⁰ These studies highlight the large sample sizes and/or long study durations needed to test agents using brain atrophy as primary outcome. In the future, precise surrogate markers of neuroprotection will be a great need for earlier phase trials. These results also suggest that targeting > 1 MOA may be necessary to treat SPMS effectively.

Efforts to promote remyelination target one hallmark of MS damage. High dose biotin (about 10,000× usual dose) may promote myelin repair as a cofactor for fatty acid synthesis and support mitochondrial oxidative phosphorylation. While a RCT yielded a greater proportion of participants with either PPMS or SPMS with improvement in disability than placebo at 12 months, an open label trial suggested otherwise indicating a need for a more definitive trial.^31,32

Anti-LINGO-1 (opicinumab) is a monoclonal antibody that targets LINGO, a potent negative regulator of oligodendrocyte differentiation and myelination.³³ Although this agent failed in a phase 2 trial in relapsing MS, and is thus unlikely to be tested in progressive forms, the innovative approach to stimulating oligodendrocytes is ongoing. One such effort is to use thyroid hormone, crucial to myelin formation during development, as a repair agent in MS.³⁴ A dose-finding study of thyroid hormone was completed and efforts to develop a thyromimetic agent are ongoing.

Finally, efforts to promote neurogenesis remain a goal for many neurodegenerative diseases. Exercise appears to prevent age-related atrophy of the hippocampus in animals and humans and help maintain neuronal health.³⁵ In patients with RRMS, cortical thickness is impacted positively by resistance training, which suggests a neuroprotective effect.³⁶ A multi-center trial of exercise in patients with progressive MS investigating cognitive outcomes is ongoing.

Discontinuing DMT

In the early 1990s, the successful development of immune modulating therapies that reliably reduced disease activity in RRMS led to widespread initiation in patients with relapsing disease. However, guidance on when or if to discontinue DMT, even in those who have transitioned to SPMS, remains largely absent at this time. Requests to discontinue DMT may come from patients weary of taking medication (especially injections), bothered by AEs, or those who no longer perceive efficacy from their treatments. Clinicians also may question the benefit of immune modulation in patients with longstanding freedom from relapses or changes in MRI lesion burden.

To inform discussion centered on treatment discontinuation, a clinical trial is currently underway to better answer the question of when and how to withdraw MS therapy. Discontinuation of Disease Modifying Therapies in Multiple Sclerosis (DISCO-MS) is a prospective, placebo-controlled RCT and its primary endpoint is recurrence of disease activity over a 2 year follow-up period.³⁷ Eligibility requirements for the trial include age > 55 years, 5-year freedom from relapses, and 3-year freedom from new MRI lesions (criteria informed by progressive MS cohort studies).³¹ In addition to demonstrating the active disease recurrence rates in this patient population, the trial also aims to identify risk factors for recurrent disease activity among treated MS patients.³⁷ DISCO-MS builds upon a series of retrospective and observational studies that partially answered these questions, albeit in the context of biases inherent in retrospective or observational studies.

A Minneapolis MS Treatment and Research Center single-center study identified 77 SPMS patients with no acute CNS inflammatory events over 2 to 20 years and advised these patients to stop taking DMT.³² In this group, 11.7% of subjects experienced recurrent active disease. Age was the primary discriminating factor. The mean age of those who experienced disease activity was 56 years vs 61 years those who did not. A second observational study from France found that among 100 SPMS patients treated either with interferon β or glatiramer acetate for at least 6 months, 35% experienced some form of inflammatory disease upon discontinuation.³⁸ Sixteen patients relapsed and 19 developed gadolinium-enhancing MR lesions after DMT discontinuation. However, the age of the cohort was younger than the Minneapolis study (47.2 years vs 61 years), and reasons for discontinuation (eg, AEs or lack of disease activity) were not considered in the analysis.

Other studies examining the safety of DMT discontinuation have not considered MS subtype or excluded patients with progressive subtypes of MS. The largest studies to date on DMT discontinuation utilized the international MSBase global patient registry, which identified nearly 5,000 patients who discontinued interferons (73%), glatiramer acetate (18%), natalizumab (6%), or fingolimod (3%), without specifying the reasons for discontinuation.³⁹ Despite these shortcomings, data reveal trends that are helpful in predicting how MS tends to behave in patients who have discontinued therapy. Not surprisingly, disability progression was most likely among patients already characterized as having a progressive phenotype, while relapses were less likely to occur among older, progressive patients.

Although clinicians may be increasingly willing to discuss DMT discontinuation with their patients, at least 1 study exploring patient perspectives on stopping treatment suggests widespread reluctance to stop treatment. A survey conducted with participants in the North American Research Committee on Multiple Sclerosis patient-report registry found that among survey respondents, only 11.9% would discontinue their MS medication if deemed stable, while 66.3% stated they were unlikely to stop treatment.⁴⁰

These results suggest that before clinicians incorporate DMT discontinuation into the normal course of discussion with patients, they should be prepared to provide both education (on the wisdom of stopping under the right circumstances) and evidence to support when and how to make the recommendation. Based on existing evidence, criteria for recommending treatment discontinuation might include prolonged freedom from disease activity (≥ 5 years), age > 55 years or 60 years, and a progressive disease course. Thus far, no combination of factors has been shown to completely predict an event-free transition off of medicine. Since no fixed algorithm yet exists to guide DMT stoppage in MS, reasonable suggestions for monitoring patients might include surveillance MRIs, more frequent clinic visits, and possible transitional treatment for patients coming off of natalizumab or fingolimod, since these drugs have been associated with rebound disease activity when discontinued.^41,42

Clinicians wishing to maximize function and quality of life for their patients at any age or stage of disease should look to nonpharmacologic interventions to lessen disability and maximize quality of life. While beyond the scope of this discussion, preliminary evidence suggests multimodal (aerobic, resistance, balance) exercise may enhance endurance and cognitive processing speed, and that treatment of comorbid diseases affecting vascular health benefits MS. ⁴³

Conclusions

The development of numerous treatments for RRMS has established an entirely new landscape and disease course for those with MS. While this benefit has not entirely extended to those with progressive MS, those with active disease with superimposed relapses may receive limited benefit from these medications. New insights into the pathophysiology of progressive MS may lead us to new treatments through multiple alternative pathophysiologic pathways. Some early studies using this strategy show promise in slowing the progressive phase. Medication development for progressive MS faces multiple challenges due to lack of a single animal model demonstrating both pathology and clinical effects, absence of phase 1 surrogate biomarkers, and later phase trial endpoints that require large sample sizes and extended study durations. Nevertheless, the increase in number of trials and diversity of therapeutic approaches for progressive MS provides hope for effective therapy. Currently, the heterogeneity of the population with progressive MS requires an individualized treatment approach, and in some of these patients, stopping therapy may be a reasonable consideration. Symptomatic management remains critical for all patients with progressive MS as well as non-pharmacologic approaches that maximize quality of life.

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system, with recent estimates of around 1 million people living with MS in the US.¹ In many countries, MS is a leading cause of disability among young adults, second only to trauma.² Clinically, neurologic worsening (ie, disability) in MS can occur in the relapsing-remitting (RRMS) phase of disease due to incomplete recovery from neuroinflammatory relapses. However, in the 15% of patients with a progressive course from onset (PPMS), and in those with RRMS who transition to a secondary progressive phenotype (SPMS), neurologic worsening follows a slowly progressive pattern.³ A progressive disease course—either PPMS at onset or transitioning to SPMS—is the dominant factor affecting MS-related neurologic disability accumulation. In particular, epidemiologic studies have shown that, in the absence of transitioning to a progressive disease course, < 5% of individuals with MS will accumulate sufficient disability to necessitate use of a cane for ambulation.^4-6 Therefore, developing disease modifying therapies (DMTs) that are highly effective at slowing or stopping the gradual accumulation of neurologic disability in progressive MS represent a critical unmet need.

Research into the development of DMTs for progressive MS has been hindered by a number of factors. In particular, the clinical definition and diagnosis of progressive MS has been an evolving concept. Diagnostic criteria for MS, which help facilitate the enrollment of appropriate subjects into clinical trials, have only recently clarified the current consensus definition for progressive MS—steadily increasing neurologic disability independent of clinical relapses. Looking back to the Schumacher criteria in 1965 and Poser criteria in 1983, it was acknowledged that neurologic symptoms in MS may follow a relapsing-remitting or progressive pattern, but little attempt was made to define progressive MS.^7,8 The original McDonald criteria in 2001 defined diagnostic criteria for progressive MS.⁹ These criteria continued to evolve through subsequent revisions (eg, cerebrospinal fluid [CSF] specific oligoclonal bands no longer are an absolute requirement), and only in the 2017 revision was it emphasized that disability progression must occur independent of clinical relapses, concordant with similar emphasis in the 2013 revision of MS clinical course definitions.^3,10

The interpretation of prior clinical trials of DMT for progressive MS must consider this evolving clinical definition. The US Food and Drug Administration (FDA) approved mitoxantrone in 2000—making it the first DMT to carry an approved label for SPMS. While achieving significant clinical efficacy, it is clear from the details of the trial that the enrolled subjects had a high degree of inflammatory disease activity, which suggests that mitoxantrone treats neuroinflammation and not relapse-independent worsening. More recently, disparate results were seen in the anti-CD20 (rituximab, ocrelizumab) and S1P receptor modulator (fingolimod, siponimod) trials targeted at patients with primary and secondary progressive MS.^11-14 Although there are differences between these therapies, they are more similar than not within the same therapeutic class. Taken together, these trials illustrate the critical impact the narrower inclusion/exclusion criteria (namely age and extent of inflammatory activity) had on attaining positive outcomes. Other considerations, such as confounding illness, also may impact trial recruitment and generalizability of findings.

The lack of known biological targets in progressive MS, which is a complex disease with an incompletely understood and heterogeneous pathology, also hinders DMT development. Decades of research has characterized multifocal central nervous system (CNS) lesions that exhibit features of demyelination, inflammation, reactive gliosis, axonal loss, and neuronal damage. Until recently, however, much of this research focused on the relapsing phase of disease, and so the understanding of the pathologic underpinnings of progressive disease has remained limited. Current areas of investigation encompass a broad range of pathological processes, such as microglial activation, meningeal lymphoid follicles, remyelination failure, vulnerability of chronically demyelinated axons, oxidative injury, iron accumulation, mitochondrial damage, and others. There is the added complication that the pathologic processes underlying progressive MS are superimposed on the CNS aging process. In particular, the transition to progressive MS and the rate of disability accumulation during progressive MS show strong correlation with age.^6,15-17

Finally, DMT development for progressive MS also is hindered by the lack of specific surrogate and clinical outcome measures. Trials for relapsing MS have benefited greatly from the relatively straightforward assessment of clinical relapses and inflammatory disease activity on magnetic resonance imaging (MRI). With the goal of developing DMTs that are highly effective at slowing or stopping the gradual accumulation of neurologic disability in progressive MS, which by definition occurs independent of clinical relapses, these measures are not directly relevant. The longitudinal clinical disability outcome measures change at a slower rate than in early, relapsing disease. The use of standardized scales (eg, the Expanded Disability Status Scale [EDSS]), lower limb function, upper limb function, cognition, or a combination is a subject of ongoing debate. For example, the ASCEND and IMPACT trials (placebo-controlled trials for SPMS with natalizumab and interferon β-1a, respectively) showed no significant impact in EDSS progression—but in both of these trials, the 9-hole peg test (9-HPT), a performance measure for upper limb function, showed significant improvement.^10,18 Particularly in those with an EDSS of > 6.5, who are unlikely to have measurable EDSS progression, functional tests such as the 9-HPT or timed 25-foot walk may be more sensitive as measures for disability progression.¹¹ MRI measures of brain atrophy is the current gold standard surrogate outcome for clinical trials in progressive MS, but others that may warrant consideration include optical coherence tomography (OCT) or CSF markers of axonal degeneration.

DMT for Progressive MS

Current diagnostic nomenclature separates patients with active (superimposed clinical and/or radiographic relapses) from those with inactive disease.^3,12 Relapsing forms of MS include all RRMS and those with SPMS with superimposed relapses (ie, active SPMS). Following this paradigm shift, the FDA changed the indication for already approved DMT from RRMS to relapsing forms of MS. Below is a discussion of DMT that specifically use the term SPMS and PPMS in the indication, where phase 3 trial data for progressive MS is available.

In 2019, the FDA approved the first oral medication (siponimod) for active SPMS. Subsequently, updates to the labels of the older DMT expanded to include active SPMS. Until 2019, the only FDA approved medication for SPMS was mitoxantrone, and use of this medication was limited due to unfavorable adverse effects (AEs). No medications had obtained FDA approval for inactive SPMS to this point, which represented an unmet need for a considerable number of patients.

Mitoxantrone became the first DMT approved for use in SPMS in 2000 following early trials that showed reductions in EDSS worsening, change in ambulation index, reduced number of treated relapses, and prolonged time to first treated relapse. However, as with some of the other positive trials in progressive MS, it is difficult to discern the impact of suppression of relapses as opposed to direct impact on progressive pathophysiology. Within the placebo arm, for example, there were 129 relapses among the 64 subjects, which suggests that these cases had particularly active disease or were in the early stages of SPMS.¹³ Furthermore, the use of this medication was limited due to concerns of cardiotoxicity and hematologic malignancy as serious AEs.

The trials of interferon β-1b illustrate the same difficulty of isolating possible benefits in disease progression from disability accumulated from relapses. The first interferon β-1b trial for SPMS, was conducted in Europe using fingolimod and showed a delay in confirmed disability progression compared to placebo as measured with the EDSS.¹⁴ However, a North American trial that followed in 2004 was unable to replicate this finding.¹⁵ The patients in the European trial appeared to be in an earlier phase of SPMS with more active disease, and a post-hoc pooled analysis suggested that patients with active disease and those with more pronounced disability progression were more likely to benefit from treatment.¹⁶ Overall, interferons do not appear to appreciably alter disability in the long-term for patients with SPMS, though they may modify short-term, relapse-related disability.

Perhaps the most encouraging data for SPMS was found in the EXPAND trial, which investigated siponimod, an S1P receptor modulator that is more selective than fingolimod. The trial identified a 21% reduction in 3-month confirmed disability progression for SPMS patients taking siponimod compared with those taking a placebo.¹⁷ Although the patients in EXPAND did seem to have relatively less disease activity at baseline than those who participated in other SPMS trials, those who benefitted from siponimod were primarily patients who had clinical and/or radiographic relapses over the prior 2 years. Based on this, the FDA approved siponimod for active SPMS. The extent to which siponimod exerts a true neuroprotective effect beyond reducing inflammation has not been clearly established.

B-cell depleting therapies rituximab and ocrelizumab have been evaluated in both primary and secondary progressive MS populations. Early investigations of the chimeric rituximab in PPMS did not show benefits on disability (EDSS) progression; however, benefits were seen in analysis of some subgroups.¹⁸ With this in mind, the ORATORIO trial for the humanized version, ocreluzimab, included PPMS patients that were younger (aged < 55 years) and had cutoffs for disease duration (< 15 years for those with EDSS more than 5 years, < 10 years for those with EDSS less than 5 years). The study showed statistically significant changes on disability progression, which led to ocrelizumab receiving the first FDA indication for PPMS.¹¹ There are substantial pathophysiologic similarities between PPMS and SPMS in the progressive phase.¹⁹ While these medications may have similar effects across these disease processes, these benefits have not yet been demonstrated in a prospective trial for the SPMS population. Regardless, B-cell depleting therapy is a reasonable consideration for select patients with active SPMS, consistent with a relapsing form of MS.

Therapies in Development 

DMT development for progressive MS is a high priority area. Current immunomodulatory therapies for RRMS have consistently been ineffective in the inactive forms of MS, with the possible exceptions of ocrelizumab and siponimod. Therefore, instead of immunosuppression, many agents currently in phase 2 and 3 clinical trials target alternative pathophysiological processes in order to provide neuroprotection, and/or promote remyelination and neurogenesis. These targets include oxidative stress (OS), non-T cell mediated inflammation, and mitochondrial/energy failure.²⁰ Below we review a selection of clinical trials testing agents following these approaches. Many agents have more than one potential mechanism of action (MOA) that could benefit progressive MS.

Lipoic acid (LA), also known as α-lipoic acid and thiotic acid, is one such agent targeting alternative pathophysiology in SPMS. LA is an endogenous agent synthesized de novo from fatty acids and cysteine as well as obtained in small amounts from foods.²¹ It has antioxidant (AO) properties including direct radical scavenging, regeneration of glutathione, and upregulation of AO enzymes via the NrF2 pathway.²² It supports mitochondria as a key cofactor for pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, and it also aids mitochondrial DNA synthesis.^21,22 Studies in experimental autoimmune encephalomyelitis, a widely used experimental mouse model of inflammatory demyelinating disease, also indicate a reduction in excessive microglial activation.²³ A phase 2 pilot randomized controlled trial (RCT) of 1200 mg LA in SPMS (n = 51) resulted in significantly less whole brain atrophy by SIENA (Structural Image Evaluation, Using Normalization, of Atrophy) at 2 years.²⁴ A follow-up multicenter trial is ongoing.

Simvastatin also targets alternative pathophysiology in SPMS. It has anti-inflammatory effects, improves vascular function, and promotes neuroprotection by reducing excitotoxicity. A phase 2 RCT demonstrated a reduction in whole brain atrophy in SPMS (n = 140), and a phase 3 trial is underway.²⁵ Ibudilast is another repurposed drug that targets alternative inflammation by inhibiting several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor and toll-like receptor 4. A phase 2 trial (n = 225) in both SPMS and PPMS also demonstrated a reduction in brain atrophy, but participants had high rates of AEs.²⁶

Lithium and riluzole promote neuroprotection by reducing excitotoxicity. Lithium is a pharmacologic active cation used as a mood stabilizer and causes inhibition of glycogen synthase kinase-3β. Animal models also indicate that lithium may decrease inflammation and positively impact neurogenesis.²⁷ A crossover pilot trial demonstrated tolerability with trends toward stabilization of EDSS and reductions in brain atrophy.²⁸ Three neuroprotective agents, riluzole (reduces glutamate excitotoxicity), fluoxetine (stimulates glycogenolysis and improves mitochondrial energy production), and amiloride (an acid-sensing ion channel blocker that opens in response to inflammation) were tested in a phase 2b multi-arm, multi-site parallel group RCT in SPMS (n = 445). The study failed to yield differences from placebo for any agent in reduction of brain volume loss.²⁹ A prior study of lamotrigine, a sodium channel blocker, also failed to find changes in brain volume loss.³⁰ These studies highlight the large sample sizes and/or long study durations needed to test agents using brain atrophy as primary outcome. In the future, precise surrogate markers of neuroprotection will be a great need for earlier phase trials. These results also suggest that targeting > 1 MOA may be necessary to treat SPMS effectively.

Efforts to promote remyelination target one hallmark of MS damage. High dose biotin (about 10,000× usual dose) may promote myelin repair as a cofactor for fatty acid synthesis and support mitochondrial oxidative phosphorylation. While a RCT yielded a greater proportion of participants with either PPMS or SPMS with improvement in disability than placebo at 12 months, an open label trial suggested otherwise indicating a need for a more definitive trial.^31,32

Anti-LINGO-1 (opicinumab) is a monoclonal antibody that targets LINGO, a potent negative regulator of oligodendrocyte differentiation and myelination.³³ Although this agent failed in a phase 2 trial in relapsing MS, and is thus unlikely to be tested in progressive forms, the innovative approach to stimulating oligodendrocytes is ongoing. One such effort is to use thyroid hormone, crucial to myelin formation during development, as a repair agent in MS.³⁴ A dose-finding study of thyroid hormone was completed and efforts to develop a thyromimetic agent are ongoing.

Finally, efforts to promote neurogenesis remain a goal for many neurodegenerative diseases. Exercise appears to prevent age-related atrophy of the hippocampus in animals and humans and help maintain neuronal health.³⁵ In patients with RRMS, cortical thickness is impacted positively by resistance training, which suggests a neuroprotective effect.³⁶ A multi-center trial of exercise in patients with progressive MS investigating cognitive outcomes is ongoing.

Discontinuing DMT

In the early 1990s, the successful development of immune modulating therapies that reliably reduced disease activity in RRMS led to widespread initiation in patients with relapsing disease. However, guidance on when or if to discontinue DMT, even in those who have transitioned to SPMS, remains largely absent at this time. Requests to discontinue DMT may come from patients weary of taking medication (especially injections), bothered by AEs, or those who no longer perceive efficacy from their treatments. Clinicians also may question the benefit of immune modulation in patients with longstanding freedom from relapses or changes in MRI lesion burden.

To inform discussion centered on treatment discontinuation, a clinical trial is currently underway to better answer the question of when and how to withdraw MS therapy. Discontinuation of Disease Modifying Therapies in Multiple Sclerosis (DISCO-MS) is a prospective, placebo-controlled RCT and its primary endpoint is recurrence of disease activity over a 2 year follow-up period.³⁷ Eligibility requirements for the trial include age > 55 years, 5-year freedom from relapses, and 3-year freedom from new MRI lesions (criteria informed by progressive MS cohort studies).³¹ In addition to demonstrating the active disease recurrence rates in this patient population, the trial also aims to identify risk factors for recurrent disease activity among treated MS patients.³⁷ DISCO-MS builds upon a series of retrospective and observational studies that partially answered these questions, albeit in the context of biases inherent in retrospective or observational studies.

A Minneapolis MS Treatment and Research Center single-center study identified 77 SPMS patients with no acute CNS inflammatory events over 2 to 20 years and advised these patients to stop taking DMT.³² In this group, 11.7% of subjects experienced recurrent active disease. Age was the primary discriminating factor. The mean age of those who experienced disease activity was 56 years vs 61 years those who did not. A second observational study from France found that among 100 SPMS patients treated either with interferon β or glatiramer acetate for at least 6 months, 35% experienced some form of inflammatory disease upon discontinuation.³⁸ Sixteen patients relapsed and 19 developed gadolinium-enhancing MR lesions after DMT discontinuation. However, the age of the cohort was younger than the Minneapolis study (47.2 years vs 61 years), and reasons for discontinuation (eg, AEs or lack of disease activity) were not considered in the analysis.

Other studies examining the safety of DMT discontinuation have not considered MS subtype or excluded patients with progressive subtypes of MS. The largest studies to date on DMT discontinuation utilized the international MSBase global patient registry, which identified nearly 5,000 patients who discontinued interferons (73%), glatiramer acetate (18%), natalizumab (6%), or fingolimod (3%), without specifying the reasons for discontinuation.³⁹ Despite these shortcomings, data reveal trends that are helpful in predicting how MS tends to behave in patients who have discontinued therapy. Not surprisingly, disability progression was most likely among patients already characterized as having a progressive phenotype, while relapses were less likely to occur among older, progressive patients.

Although clinicians may be increasingly willing to discuss DMT discontinuation with their patients, at least 1 study exploring patient perspectives on stopping treatment suggests widespread reluctance to stop treatment. A survey conducted with participants in the North American Research Committee on Multiple Sclerosis patient-report registry found that among survey respondents, only 11.9% would discontinue their MS medication if deemed stable, while 66.3% stated they were unlikely to stop treatment.⁴⁰

These results suggest that before clinicians incorporate DMT discontinuation into the normal course of discussion with patients, they should be prepared to provide both education (on the wisdom of stopping under the right circumstances) and evidence to support when and how to make the recommendation. Based on existing evidence, criteria for recommending treatment discontinuation might include prolonged freedom from disease activity (≥ 5 years), age > 55 years or 60 years, and a progressive disease course. Thus far, no combination of factors has been shown to completely predict an event-free transition off of medicine. Since no fixed algorithm yet exists to guide DMT stoppage in MS, reasonable suggestions for monitoring patients might include surveillance MRIs, more frequent clinic visits, and possible transitional treatment for patients coming off of natalizumab or fingolimod, since these drugs have been associated with rebound disease activity when discontinued.^41,42

Clinicians wishing to maximize function and quality of life for their patients at any age or stage of disease should look to nonpharmacologic interventions to lessen disability and maximize quality of life. While beyond the scope of this discussion, preliminary evidence suggests multimodal (aerobic, resistance, balance) exercise may enhance endurance and cognitive processing speed, and that treatment of comorbid diseases affecting vascular health benefits MS. ⁴³

Conclusions

The development of numerous treatments for RRMS has established an entirely new landscape and disease course for those with MS. While this benefit has not entirely extended to those with progressive MS, those with active disease with superimposed relapses may receive limited benefit from these medications. New insights into the pathophysiology of progressive MS may lead us to new treatments through multiple alternative pathophysiologic pathways. Some early studies using this strategy show promise in slowing the progressive phase. Medication development for progressive MS faces multiple challenges due to lack of a single animal model demonstrating both pathology and clinical effects, absence of phase 1 surrogate biomarkers, and later phase trial endpoints that require large sample sizes and extended study durations. Nevertheless, the increase in number of trials and diversity of therapeutic approaches for progressive MS provides hope for effective therapy. Currently, the heterogeneity of the population with progressive MS requires an individualized treatment approach, and in some of these patients, stopping therapy may be a reasonable consideration. Symptomatic management remains critical for all patients with progressive MS as well as non-pharmacologic approaches that maximize quality of life.

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system, with recent estimates of around 1 million people living with MS in the US.¹ In many countries, MS is a leading cause of disability among young adults, second only to trauma.² Clinically, neurologic worsening (ie, disability) in MS can occur in the relapsing-remitting (RRMS) phase of disease due to incomplete recovery from neuroinflammatory relapses. However, in the 15% of patients with a progressive course from onset (PPMS), and in those with RRMS who transition to a secondary progressive phenotype (SPMS), neurologic worsening follows a slowly progressive pattern.³ A progressive disease course—either PPMS at onset or transitioning to SPMS—is the dominant factor affecting MS-related neurologic disability accumulation. In particular, epidemiologic studies have shown that, in the absence of transitioning to a progressive disease course, < 5% of individuals with MS will accumulate sufficient disability to necessitate use of a cane for ambulation.^4-6 Therefore, developing disease modifying therapies (DMTs) that are highly effective at slowing or stopping the gradual accumulation of neurologic disability in progressive MS represent a critical unmet need.

Research into the development of DMTs for progressive MS has been hindered by a number of factors. In particular, the clinical definition and diagnosis of progressive MS has been an evolving concept. Diagnostic criteria for MS, which help facilitate the enrollment of appropriate subjects into clinical trials, have only recently clarified the current consensus definition for progressive MS—steadily increasing neurologic disability independent of clinical relapses. Looking back to the Schumacher criteria in 1965 and Poser criteria in 1983, it was acknowledged that neurologic symptoms in MS may follow a relapsing-remitting or progressive pattern, but little attempt was made to define progressive MS.^7,8 The original McDonald criteria in 2001 defined diagnostic criteria for progressive MS.⁹ These criteria continued to evolve through subsequent revisions (eg, cerebrospinal fluid [CSF] specific oligoclonal bands no longer are an absolute requirement), and only in the 2017 revision was it emphasized that disability progression must occur independent of clinical relapses, concordant with similar emphasis in the 2013 revision of MS clinical course definitions.^3,10

The interpretation of prior clinical trials of DMT for progressive MS must consider this evolving clinical definition. The US Food and Drug Administration (FDA) approved mitoxantrone in 2000—making it the first DMT to carry an approved label for SPMS. While achieving significant clinical efficacy, it is clear from the details of the trial that the enrolled subjects had a high degree of inflammatory disease activity, which suggests that mitoxantrone treats neuroinflammation and not relapse-independent worsening. More recently, disparate results were seen in the anti-CD20 (rituximab, ocrelizumab) and S1P receptor modulator (fingolimod, siponimod) trials targeted at patients with primary and secondary progressive MS.^11-14 Although there are differences between these therapies, they are more similar than not within the same therapeutic class. Taken together, these trials illustrate the critical impact the narrower inclusion/exclusion criteria (namely age and extent of inflammatory activity) had on attaining positive outcomes. Other considerations, such as confounding illness, also may impact trial recruitment and generalizability of findings.

The lack of known biological targets in progressive MS, which is a complex disease with an incompletely understood and heterogeneous pathology, also hinders DMT development. Decades of research has characterized multifocal central nervous system (CNS) lesions that exhibit features of demyelination, inflammation, reactive gliosis, axonal loss, and neuronal damage. Until recently, however, much of this research focused on the relapsing phase of disease, and so the understanding of the pathologic underpinnings of progressive disease has remained limited. Current areas of investigation encompass a broad range of pathological processes, such as microglial activation, meningeal lymphoid follicles, remyelination failure, vulnerability of chronically demyelinated axons, oxidative injury, iron accumulation, mitochondrial damage, and others. There is the added complication that the pathologic processes underlying progressive MS are superimposed on the CNS aging process. In particular, the transition to progressive MS and the rate of disability accumulation during progressive MS show strong correlation with age.^6,15-17

Finally, DMT development for progressive MS also is hindered by the lack of specific surrogate and clinical outcome measures. Trials for relapsing MS have benefited greatly from the relatively straightforward assessment of clinical relapses and inflammatory disease activity on magnetic resonance imaging (MRI). With the goal of developing DMTs that are highly effective at slowing or stopping the gradual accumulation of neurologic disability in progressive MS, which by definition occurs independent of clinical relapses, these measures are not directly relevant. The longitudinal clinical disability outcome measures change at a slower rate than in early, relapsing disease. The use of standardized scales (eg, the Expanded Disability Status Scale [EDSS]), lower limb function, upper limb function, cognition, or a combination is a subject of ongoing debate. For example, the ASCEND and IMPACT trials (placebo-controlled trials for SPMS with natalizumab and interferon β-1a, respectively) showed no significant impact in EDSS progression—but in both of these trials, the 9-hole peg test (9-HPT), a performance measure for upper limb function, showed significant improvement.^10,18 Particularly in those with an EDSS of > 6.5, who are unlikely to have measurable EDSS progression, functional tests such as the 9-HPT or timed 25-foot walk may be more sensitive as measures for disability progression.¹¹ MRI measures of brain atrophy is the current gold standard surrogate outcome for clinical trials in progressive MS, but others that may warrant consideration include optical coherence tomography (OCT) or CSF markers of axonal degeneration.

DMT for Progressive MS

Current diagnostic nomenclature separates patients with active (superimposed clinical and/or radiographic relapses) from those with inactive disease.^3,12 Relapsing forms of MS include all RRMS and those with SPMS with superimposed relapses (ie, active SPMS). Following this paradigm shift, the FDA changed the indication for already approved DMT from RRMS to relapsing forms of MS. Below is a discussion of DMT that specifically use the term SPMS and PPMS in the indication, where phase 3 trial data for progressive MS is available.

In 2019, the FDA approved the first oral medication (siponimod) for active SPMS. Subsequently, updates to the labels of the older DMT expanded to include active SPMS. Until 2019, the only FDA approved medication for SPMS was mitoxantrone, and use of this medication was limited due to unfavorable adverse effects (AEs). No medications had obtained FDA approval for inactive SPMS to this point, which represented an unmet need for a considerable number of patients.

Mitoxantrone became the first DMT approved for use in SPMS in 2000 following early trials that showed reductions in EDSS worsening, change in ambulation index, reduced number of treated relapses, and prolonged time to first treated relapse. However, as with some of the other positive trials in progressive MS, it is difficult to discern the impact of suppression of relapses as opposed to direct impact on progressive pathophysiology. Within the placebo arm, for example, there were 129 relapses among the 64 subjects, which suggests that these cases had particularly active disease or were in the early stages of SPMS.¹³ Furthermore, the use of this medication was limited due to concerns of cardiotoxicity and hematologic malignancy as serious AEs.

The trials of interferon β-1b illustrate the same difficulty of isolating possible benefits in disease progression from disability accumulated from relapses. The first interferon β-1b trial for SPMS, was conducted in Europe using fingolimod and showed a delay in confirmed disability progression compared to placebo as measured with the EDSS.¹⁴ However, a North American trial that followed in 2004 was unable to replicate this finding.¹⁵ The patients in the European trial appeared to be in an earlier phase of SPMS with more active disease, and a post-hoc pooled analysis suggested that patients with active disease and those with more pronounced disability progression were more likely to benefit from treatment.¹⁶ Overall, interferons do not appear to appreciably alter disability in the long-term for patients with SPMS, though they may modify short-term, relapse-related disability.

Perhaps the most encouraging data for SPMS was found in the EXPAND trial, which investigated siponimod, an S1P receptor modulator that is more selective than fingolimod. The trial identified a 21% reduction in 3-month confirmed disability progression for SPMS patients taking siponimod compared with those taking a placebo.¹⁷ Although the patients in EXPAND did seem to have relatively less disease activity at baseline than those who participated in other SPMS trials, those who benefitted from siponimod were primarily patients who had clinical and/or radiographic relapses over the prior 2 years. Based on this, the FDA approved siponimod for active SPMS. The extent to which siponimod exerts a true neuroprotective effect beyond reducing inflammation has not been clearly established.

B-cell depleting therapies rituximab and ocrelizumab have been evaluated in both primary and secondary progressive MS populations. Early investigations of the chimeric rituximab in PPMS did not show benefits on disability (EDSS) progression; however, benefits were seen in analysis of some subgroups.¹⁸ With this in mind, the ORATORIO trial for the humanized version, ocreluzimab, included PPMS patients that were younger (aged < 55 years) and had cutoffs for disease duration (< 15 years for those with EDSS more than 5 years, < 10 years for those with EDSS less than 5 years). The study showed statistically significant changes on disability progression, which led to ocrelizumab receiving the first FDA indication for PPMS.¹¹ There are substantial pathophysiologic similarities between PPMS and SPMS in the progressive phase.¹⁹ While these medications may have similar effects across these disease processes, these benefits have not yet been demonstrated in a prospective trial for the SPMS population. Regardless, B-cell depleting therapy is a reasonable consideration for select patients with active SPMS, consistent with a relapsing form of MS.

Therapies in Development 

DMT development for progressive MS is a high priority area. Current immunomodulatory therapies for RRMS have consistently been ineffective in the inactive forms of MS, with the possible exceptions of ocrelizumab and siponimod. Therefore, instead of immunosuppression, many agents currently in phase 2 and 3 clinical trials target alternative pathophysiological processes in order to provide neuroprotection, and/or promote remyelination and neurogenesis. These targets include oxidative stress (OS), non-T cell mediated inflammation, and mitochondrial/energy failure.²⁰ Below we review a selection of clinical trials testing agents following these approaches. Many agents have more than one potential mechanism of action (MOA) that could benefit progressive MS.

Lipoic acid (LA), also known as α-lipoic acid and thiotic acid, is one such agent targeting alternative pathophysiology in SPMS. LA is an endogenous agent synthesized de novo from fatty acids and cysteine as well as obtained in small amounts from foods.²¹ It has antioxidant (AO) properties including direct radical scavenging, regeneration of glutathione, and upregulation of AO enzymes via the NrF2 pathway.²² It supports mitochondria as a key cofactor for pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, and it also aids mitochondrial DNA synthesis.^21,22 Studies in experimental autoimmune encephalomyelitis, a widely used experimental mouse model of inflammatory demyelinating disease, also indicate a reduction in excessive microglial activation.²³ A phase 2 pilot randomized controlled trial (RCT) of 1200 mg LA in SPMS (n = 51) resulted in significantly less whole brain atrophy by SIENA (Structural Image Evaluation, Using Normalization, of Atrophy) at 2 years.²⁴ A follow-up multicenter trial is ongoing.

Simvastatin also targets alternative pathophysiology in SPMS. It has anti-inflammatory effects, improves vascular function, and promotes neuroprotection by reducing excitotoxicity. A phase 2 RCT demonstrated a reduction in whole brain atrophy in SPMS (n = 140), and a phase 3 trial is underway.²⁵ Ibudilast is another repurposed drug that targets alternative inflammation by inhibiting several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor and toll-like receptor 4. A phase 2 trial (n = 225) in both SPMS and PPMS also demonstrated a reduction in brain atrophy, but participants had high rates of AEs.²⁶

Lithium and riluzole promote neuroprotection by reducing excitotoxicity. Lithium is a pharmacologic active cation used as a mood stabilizer and causes inhibition of glycogen synthase kinase-3β. Animal models also indicate that lithium may decrease inflammation and positively impact neurogenesis.²⁷ A crossover pilot trial demonstrated tolerability with trends toward stabilization of EDSS and reductions in brain atrophy.²⁸ Three neuroprotective agents, riluzole (reduces glutamate excitotoxicity), fluoxetine (stimulates glycogenolysis and improves mitochondrial energy production), and amiloride (an acid-sensing ion channel blocker that opens in response to inflammation) were tested in a phase 2b multi-arm, multi-site parallel group RCT in SPMS (n = 445). The study failed to yield differences from placebo for any agent in reduction of brain volume loss.²⁹ A prior study of lamotrigine, a sodium channel blocker, also failed to find changes in brain volume loss.³⁰ These studies highlight the large sample sizes and/or long study durations needed to test agents using brain atrophy as primary outcome. In the future, precise surrogate markers of neuroprotection will be a great need for earlier phase trials. These results also suggest that targeting > 1 MOA may be necessary to treat SPMS effectively.

Efforts to promote remyelination target one hallmark of MS damage. High dose biotin (about 10,000× usual dose) may promote myelin repair as a cofactor for fatty acid synthesis and support mitochondrial oxidative phosphorylation. While a RCT yielded a greater proportion of participants with either PPMS or SPMS with improvement in disability than placebo at 12 months, an open label trial suggested otherwise indicating a need for a more definitive trial.^31,32

Anti-LINGO-1 (opicinumab) is a monoclonal antibody that targets LINGO, a potent negative regulator of oligodendrocyte differentiation and myelination.³³ Although this agent failed in a phase 2 trial in relapsing MS, and is thus unlikely to be tested in progressive forms, the innovative approach to stimulating oligodendrocytes is ongoing. One such effort is to use thyroid hormone, crucial to myelin formation during development, as a repair agent in MS.³⁴ A dose-finding study of thyroid hormone was completed and efforts to develop a thyromimetic agent are ongoing.

Finally, efforts to promote neurogenesis remain a goal for many neurodegenerative diseases. Exercise appears to prevent age-related atrophy of the hippocampus in animals and humans and help maintain neuronal health.³⁵ In patients with RRMS, cortical thickness is impacted positively by resistance training, which suggests a neuroprotective effect.³⁶ A multi-center trial of exercise in patients with progressive MS investigating cognitive outcomes is ongoing.

Discontinuing DMT

In the early 1990s, the successful development of immune modulating therapies that reliably reduced disease activity in RRMS led to widespread initiation in patients with relapsing disease. However, guidance on when or if to discontinue DMT, even in those who have transitioned to SPMS, remains largely absent at this time. Requests to discontinue DMT may come from patients weary of taking medication (especially injections), bothered by AEs, or those who no longer perceive efficacy from their treatments. Clinicians also may question the benefit of immune modulation in patients with longstanding freedom from relapses or changes in MRI lesion burden.

To inform discussion centered on treatment discontinuation, a clinical trial is currently underway to better answer the question of when and how to withdraw MS therapy. Discontinuation of Disease Modifying Therapies in Multiple Sclerosis (DISCO-MS) is a prospective, placebo-controlled RCT and its primary endpoint is recurrence of disease activity over a 2 year follow-up period.³⁷ Eligibility requirements for the trial include age > 55 years, 5-year freedom from relapses, and 3-year freedom from new MRI lesions (criteria informed by progressive MS cohort studies).³¹ In addition to demonstrating the active disease recurrence rates in this patient population, the trial also aims to identify risk factors for recurrent disease activity among treated MS patients.³⁷ DISCO-MS builds upon a series of retrospective and observational studies that partially answered these questions, albeit in the context of biases inherent in retrospective or observational studies.

A Minneapolis MS Treatment and Research Center single-center study identified 77 SPMS patients with no acute CNS inflammatory events over 2 to 20 years and advised these patients to stop taking DMT.³² In this group, 11.7% of subjects experienced recurrent active disease. Age was the primary discriminating factor. The mean age of those who experienced disease activity was 56 years vs 61 years those who did not. A second observational study from France found that among 100 SPMS patients treated either with interferon β or glatiramer acetate for at least 6 months, 35% experienced some form of inflammatory disease upon discontinuation.³⁸ Sixteen patients relapsed and 19 developed gadolinium-enhancing MR lesions after DMT discontinuation. However, the age of the cohort was younger than the Minneapolis study (47.2 years vs 61 years), and reasons for discontinuation (eg, AEs or lack of disease activity) were not considered in the analysis.

Other studies examining the safety of DMT discontinuation have not considered MS subtype or excluded patients with progressive subtypes of MS. The largest studies to date on DMT discontinuation utilized the international MSBase global patient registry, which identified nearly 5,000 patients who discontinued interferons (73%), glatiramer acetate (18%), natalizumab (6%), or fingolimod (3%), without specifying the reasons for discontinuation.³⁹ Despite these shortcomings, data reveal trends that are helpful in predicting how MS tends to behave in patients who have discontinued therapy. Not surprisingly, disability progression was most likely among patients already characterized as having a progressive phenotype, while relapses were less likely to occur among older, progressive patients.

Although clinicians may be increasingly willing to discuss DMT discontinuation with their patients, at least 1 study exploring patient perspectives on stopping treatment suggests widespread reluctance to stop treatment. A survey conducted with participants in the North American Research Committee on Multiple Sclerosis patient-report registry found that among survey respondents, only 11.9% would discontinue their MS medication if deemed stable, while 66.3% stated they were unlikely to stop treatment.⁴⁰

These results suggest that before clinicians incorporate DMT discontinuation into the normal course of discussion with patients, they should be prepared to provide both education (on the wisdom of stopping under the right circumstances) and evidence to support when and how to make the recommendation. Based on existing evidence, criteria for recommending treatment discontinuation might include prolonged freedom from disease activity (≥ 5 years), age > 55 years or 60 years, and a progressive disease course. Thus far, no combination of factors has been shown to completely predict an event-free transition off of medicine. Since no fixed algorithm yet exists to guide DMT stoppage in MS, reasonable suggestions for monitoring patients might include surveillance MRIs, more frequent clinic visits, and possible transitional treatment for patients coming off of natalizumab or fingolimod, since these drugs have been associated with rebound disease activity when discontinued.^41,42

Clinicians wishing to maximize function and quality of life for their patients at any age or stage of disease should look to nonpharmacologic interventions to lessen disability and maximize quality of life. While beyond the scope of this discussion, preliminary evidence suggests multimodal (aerobic, resistance, balance) exercise may enhance endurance and cognitive processing speed, and that treatment of comorbid diseases affecting vascular health benefits MS. ⁴³

Conclusions

The development of numerous treatments for RRMS has established an entirely new landscape and disease course for those with MS. While this benefit has not entirely extended to those with progressive MS, those with active disease with superimposed relapses may receive limited benefit from these medications. New insights into the pathophysiology of progressive MS may lead us to new treatments through multiple alternative pathophysiologic pathways. Some early studies using this strategy show promise in slowing the progressive phase. Medication development for progressive MS faces multiple challenges due to lack of a single animal model demonstrating both pathology and clinical effects, absence of phase 1 surrogate biomarkers, and later phase trial endpoints that require large sample sizes and extended study durations. Nevertheless, the increase in number of trials and diversity of therapeutic approaches for progressive MS provides hope for effective therapy. Currently, the heterogeneity of the population with progressive MS requires an individualized treatment approach, and in some of these patients, stopping therapy may be a reasonable consideration. Symptomatic management remains critical for all patients with progressive MS as well as non-pharmacologic approaches that maximize quality of life.