About 15 million doses of the Johnson & Johnson COVID-19 vaccine were ruined after workers at a manufacturing plant mixed up ingredients, The New York Times reported.

The Baltimore plant is operated by a company called Emergent BioSolutions, the Times said. The company works with both Johnson & Johnson and AstraZeneca.

The mistake has stopped shipments of the vaccine until the FDA investigates, the paper said. The mishap, however, does not affect doses of the J&J one-shot vaccine already delivered and being used.

The problem is that tens of millions of doses were supposed to come from the Baltimore plant.

The Associated Press reported that Emergent has had numerous problems with the FDA, with the agency citing the company for poorly trained employees, cracked vials and mold.

The records cover inspections at Emergent facilities, including Bayview, since 2017. Following a December 2017 inspection at an Emergent plant in Canton, Massachusetts, the FDA said the company hadn’t corrected “continued low level mold and yeast isolates” found in the facility. Nearly a year later, agency investigators questioned why Emergent had “an unwritten policy of not conducting routine compliance audits” at a separate plant in Baltimore, known as Camden, where an anthrax vaccine is filled into vials.

Meanwhile, in a statement, Johnson & Johnson said its own quality control process identified the problem in one batch of ingredients. The company said the Emergent plant in Baltimore is “not yet authorized to manufacture drug substance for our COVID-19 vaccine. This batch was never advanced to the filling and finishing stages of our manufacturing process.”

The company said it plans to still seek emergency use authorization for a different Emergent facility and will provide more experts on site at Emergent.

The Times reports that President Joe Biden’s team still believes the administration can meet its commitment to have enough vaccine doses to immunize every adult by the end of May.

Johnson & Johnson said it still plans to deliver an additional 24 million doses through April.

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

This article was updated 4/1/21.

About 15 million doses of the Johnson & Johnson COVID-19 vaccine were ruined after workers at a manufacturing plant mixed up ingredients, The New York Times reported.

The Baltimore plant is operated by a company called Emergent BioSolutions, the Times said. The company works with both Johnson & Johnson and AstraZeneca.

The mistake has stopped shipments of the vaccine until the FDA investigates, the paper said. The mishap, however, does not affect doses of the J&J one-shot vaccine already delivered and being used.

The problem is that tens of millions of doses were supposed to come from the Baltimore plant.

The Associated Press reported that Emergent has had numerous problems with the FDA, with the agency citing the company for poorly trained employees, cracked vials and mold.

The records cover inspections at Emergent facilities, including Bayview, since 2017. Following a December 2017 inspection at an Emergent plant in Canton, Massachusetts, the FDA said the company hadn’t corrected “continued low level mold and yeast isolates” found in the facility. Nearly a year later, agency investigators questioned why Emergent had “an unwritten policy of not conducting routine compliance audits” at a separate plant in Baltimore, known as Camden, where an anthrax vaccine is filled into vials.

Meanwhile, in a statement, Johnson & Johnson said its own quality control process identified the problem in one batch of ingredients. The company said the Emergent plant in Baltimore is “not yet authorized to manufacture drug substance for our COVID-19 vaccine. This batch was never advanced to the filling and finishing stages of our manufacturing process.”

The company said it plans to still seek emergency use authorization for a different Emergent facility and will provide more experts on site at Emergent.

The Times reports that President Joe Biden’s team still believes the administration can meet its commitment to have enough vaccine doses to immunize every adult by the end of May.

Johnson & Johnson said it still plans to deliver an additional 24 million doses through April.

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

This article was updated 4/1/21.

About 15 million doses of the Johnson & Johnson COVID-19 vaccine were ruined after workers at a manufacturing plant mixed up ingredients, The New York Times reported.

The Baltimore plant is operated by a company called Emergent BioSolutions, the Times said. The company works with both Johnson & Johnson and AstraZeneca.

The mistake has stopped shipments of the vaccine until the FDA investigates, the paper said. The mishap, however, does not affect doses of the J&J one-shot vaccine already delivered and being used.

The problem is that tens of millions of doses were supposed to come from the Baltimore plant.

The Associated Press reported that Emergent has had numerous problems with the FDA, with the agency citing the company for poorly trained employees, cracked vials and mold.

The records cover inspections at Emergent facilities, including Bayview, since 2017. Following a December 2017 inspection at an Emergent plant in Canton, Massachusetts, the FDA said the company hadn’t corrected “continued low level mold and yeast isolates” found in the facility. Nearly a year later, agency investigators questioned why Emergent had “an unwritten policy of not conducting routine compliance audits” at a separate plant in Baltimore, known as Camden, where an anthrax vaccine is filled into vials.

Meanwhile, in a statement, Johnson & Johnson said its own quality control process identified the problem in one batch of ingredients. The company said the Emergent plant in Baltimore is “not yet authorized to manufacture drug substance for our COVID-19 vaccine. This batch was never advanced to the filling and finishing stages of our manufacturing process.”

The company said it plans to still seek emergency use authorization for a different Emergent facility and will provide more experts on site at Emergent.

The Times reports that President Joe Biden’s team still believes the administration can meet its commitment to have enough vaccine doses to immunize every adult by the end of May.

Johnson & Johnson said it still plans to deliver an additional 24 million doses through April.

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

This article was updated 4/1/21.

Ob.Gyn. News acknowledges the passing of Charles B. Hammond, MD, a longtime editorial board member, who died on Feb. 1, 2021.

Courtesy Dr. Charles B. Hammond

Dr. Hammond served on the Ob.Gyn. News Advisory Board for 33 years. His service as a board member was one of many leadership roles to which he dedicated his time and expertise. Dr. Hammond served as president of the American College of Obstetrics & Gynecology (ACOG) from 2002 to 2003, and received a Lifetime Achievement Award from ACOG in 2015. He also served as president of the American Society of Reproductive Medicine, president of the American Gynecological and Obstetrical Society, and president of the North Carolina Obstetrical and Gynecological Society.

Dr. Hammond was honored by Duke University, Durham, N.C., as E.C. Hamblen Professor Emeritus in 2010, after more than 40 years in academia. He held the title of Edwin Crowell Hamblen Distinguished Professor of Reproductive Biology and Family Planning and Chair of the Department of Obstetrics & Gynecology from 1980 to 2002. During this time, he distinguished himself for his work in pioneering treatments for gestational trophoblastic disease. As an extension of this research, he was a founder of the Southeast Regional Trophoblastic Disease Center. In addition, Dr. Hammond was often consulted for his expertise on issues related to menopause and hormone replacement therapy.

Dr. Hammond began his medical career at Duke University after graduating from The Citadel with a bachelor of science degree in 1958. After earning his medical degree in 1961, he remained at Duke as a resident in obstetrics and gynecology, followed by completion of a fellowship in reproductive endocrinology in 1964. From 1964 to 1966, he served at the National Institutes of Health as a fellow in the National Cancer Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

A few years later, in 1969, Dr. Hammond launched his long and distinguished academic career with an assistant professor position in the department of obstetrics & gynecology at Duke.

Dr. Hammond’s many honors include a National Association for Women’s Health Lifetime Achievement Award and membership in the Institute of Medicine, now the National Academy of Medicine. He also was named a fellow of the Royal College of Obstetricians and Gynaecologists, and an honorary member of the Canadian Society of Obstetrics and Gynecology. Dr. Hammond will be remembered not only as a physician, researcher, educator, and mentor, but also an advocate for women’s health.

Ob.Gyn. News acknowledges the passing of Charles B. Hammond, MD, a longtime editorial board member, who died on Feb. 1, 2021.

Courtesy Dr. Charles B. Hammond

Dr. Hammond served on the Ob.Gyn. News Advisory Board for 33 years. His service as a board member was one of many leadership roles to which he dedicated his time and expertise. Dr. Hammond served as president of the American College of Obstetrics & Gynecology (ACOG) from 2002 to 2003, and received a Lifetime Achievement Award from ACOG in 2015. He also served as president of the American Society of Reproductive Medicine, president of the American Gynecological and Obstetrical Society, and president of the North Carolina Obstetrical and Gynecological Society.

Dr. Hammond was honored by Duke University, Durham, N.C., as E.C. Hamblen Professor Emeritus in 2010, after more than 40 years in academia. He held the title of Edwin Crowell Hamblen Distinguished Professor of Reproductive Biology and Family Planning and Chair of the Department of Obstetrics & Gynecology from 1980 to 2002. During this time, he distinguished himself for his work in pioneering treatments for gestational trophoblastic disease. As an extension of this research, he was a founder of the Southeast Regional Trophoblastic Disease Center. In addition, Dr. Hammond was often consulted for his expertise on issues related to menopause and hormone replacement therapy.

Dr. Hammond began his medical career at Duke University after graduating from The Citadel with a bachelor of science degree in 1958. After earning his medical degree in 1961, he remained at Duke as a resident in obstetrics and gynecology, followed by completion of a fellowship in reproductive endocrinology in 1964. From 1964 to 1966, he served at the National Institutes of Health as a fellow in the National Cancer Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

A few years later, in 1969, Dr. Hammond launched his long and distinguished academic career with an assistant professor position in the department of obstetrics & gynecology at Duke.

Dr. Hammond’s many honors include a National Association for Women’s Health Lifetime Achievement Award and membership in the Institute of Medicine, now the National Academy of Medicine. He also was named a fellow of the Royal College of Obstetricians and Gynaecologists, and an honorary member of the Canadian Society of Obstetrics and Gynecology. Dr. Hammond will be remembered not only as a physician, researcher, educator, and mentor, but also an advocate for women’s health.

Ob.Gyn. News acknowledges the passing of Charles B. Hammond, MD, a longtime editorial board member, who died on Feb. 1, 2021.

Courtesy Dr. Charles B. Hammond

Dr. Hammond served on the Ob.Gyn. News Advisory Board for 33 years. His service as a board member was one of many leadership roles to which he dedicated his time and expertise. Dr. Hammond served as president of the American College of Obstetrics & Gynecology (ACOG) from 2002 to 2003, and received a Lifetime Achievement Award from ACOG in 2015. He also served as president of the American Society of Reproductive Medicine, president of the American Gynecological and Obstetrical Society, and president of the North Carolina Obstetrical and Gynecological Society.

Dr. Hammond was honored by Duke University, Durham, N.C., as E.C. Hamblen Professor Emeritus in 2010, after more than 40 years in academia. He held the title of Edwin Crowell Hamblen Distinguished Professor of Reproductive Biology and Family Planning and Chair of the Department of Obstetrics & Gynecology from 1980 to 2002. During this time, he distinguished himself for his work in pioneering treatments for gestational trophoblastic disease. As an extension of this research, he was a founder of the Southeast Regional Trophoblastic Disease Center. In addition, Dr. Hammond was often consulted for his expertise on issues related to menopause and hormone replacement therapy.

Dr. Hammond began his medical career at Duke University after graduating from The Citadel with a bachelor of science degree in 1958. After earning his medical degree in 1961, he remained at Duke as a resident in obstetrics and gynecology, followed by completion of a fellowship in reproductive endocrinology in 1964. From 1964 to 1966, he served at the National Institutes of Health as a fellow in the National Cancer Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

A few years later, in 1969, Dr. Hammond launched his long and distinguished academic career with an assistant professor position in the department of obstetrics & gynecology at Duke.

Dr. Hammond’s many honors include a National Association for Women’s Health Lifetime Achievement Award and membership in the Institute of Medicine, now the National Academy of Medicine. He also was named a fellow of the Royal College of Obstetricians and Gynaecologists, and an honorary member of the Canadian Society of Obstetrics and Gynecology. Dr. Hammond will be remembered not only as a physician, researcher, educator, and mentor, but also an advocate for women’s health.

If everything goes as planned, the Pfizer and Moderna mRNA COVID-19 vaccines could be granted emergency use authorization (EUA) for children aged 12 years and older by the fall of 2021.

Courtesy Dr. Maldonado

According to Yvonne Maldonado, MD, Pfizer has fully enrolled adolescent trials and Moderna is currently enrolling 3,000 adolescents in a safety and reactogenicity trial known as TeenCOVE, in which participants will receive an intramuscular injection of 100 mcg mRNA-1273 on day 1 and on day 29. Meanwhile, Johnson & Johnson and AstraZeneca will be starting to enroll older children and adolescents into studies within the next several weeks.

The companies are also planning to enroll younger children, Dr. Maldonado, the Taube professor of global health and infectious diseases at Stanford (Calif.) University, said during the Society for Pediatric Dermatology pre-AAD meeting. “At least two of the vaccine companies have indicated that they would like to start enrolling children as young as 2-5 years of age and eventually getting down to infants and toddlers if the vaccines prove to be safe and effective in the older children. Eventually, we hope to get to the level where we can have several vaccine candidates for all children 6 months of age and older.”

In the future, she said, infectious disease experts hope to see antiviral, immunomodulatory, anti-inflammatory, and monoclonal therapies for all populations including children, although trials in this population have not begun. “Clinical trials must be flexible and adaptive to deal with children and adolescents,” added Dr. Maldonado, who is also senior associate dean for faculty development and diversity at Stanford.

“We would ideally like to have new correlates of protection, as well as biomarkers to follow for evidence of effectiveness. We also would love to see vaccines in the pediatric population as soon as possible, because herd immunity is the ultimate goal for protection against this disease and prevention of additional transmission over time.” However, she said, the degree and durability of immunity has yet to be determined, and vaccine-associated immune effects are unknown. In the meantime, infectious disease researchers expect nonpharmacologic interventions, such as wearing face masks and social distancing to continue for an undefined period.

(Less than 2 weeks after Dr. Maldonado spoke at the SPD meeting, Pfizer announced in a press release that, in phase 3 clinical trials, the company’s coronavirus vaccine was 100% effective in protecting children aged 12-15 years from infection, with a “robust” antibody responses and side effects similar to those experienced by those aged 16-25 years. The company also announced that it plans to seek Food and Drug Administration EUA for this age group. Asked to comment on this update, Dr. Maldonado said the results released by Pfizer “suggest that their COVID-19 vaccine is very safe and highly effective in preventing COVID-19 among children 12-15 years of age.” She added that additional data from the Pfizer trials as well as from Moderna and Johnson & Johnson vaccine trials “will hopefully lead to FDA EUA review in the coming weeks,” and that COVID-19 vaccinations for children “may be possible by this summer.”)
 

_{Children with underlying diseases or on immune suppressants}

At the SPD meeting, an attendee asked if there were any pediatric patients for whom she would not recommend receiving a COVID-19 vaccine because of an underlying disease or concurrent therapy with immune suppressants. “We don’t have those data yet,” Dr. Maldonado said. “Based on what we’re seeing with adults, it does appear that those with underlying conditions are at somewhat higher risk of developing severe infection and may therefore most likely to need vaccination. Most of those risks are cardiovascular, obesity, and other factors, but not necessarily immunocompromising conditions. More likely what we’re seeing is that people with underlying immunocompromising conditions may not mount a good response to the vaccines at this time. It doesn’t mean we shouldn’t give the vaccines, but we need to learn more about that.”

Dr. Maldonado went on to note that, as vaccine manufacturers commence pediatric trials, healthy children will be tested first, followed in due time with children who have immunocompromised conditions. “The question will be whether or not we should give monoclonal antibodies to those particular children to help boost their immunity to SARS-CoV-2, because they might not have a good response to the vaccines,” she said. “Those things need to be sorted out, but there’s no safety signal or concerns at this point for vaccine to be given to immunocompromised individuals.”

Another meeting attendee asked Dr. Maldonado if she thinks there is a practical role for assessing markers of T-cell immunity when evaluating suspected COVID-19 patients who may test negative on serology, Dr. Maldonado said that she and her colleagues are seeking pediatric patients who were treated for COVID-19 at Stanford, in an effort to sort this out.

They are checking peripheral blood mononuclear cells in these patients “to try and tease out what the immune response is in kids who have serious disease, versus those who came in with acute disease, versus those who are asymptomatic,” and comparing them with children who don’t have infection, she explained. “The question is, what is the role of T cells and how much do they contribute? One of the biggest questions we have is, do we have an immune correlate? Can we detect a particular level of neutralizing antibody that seems to be protective? If so, how long is it protective, and can we look for T- and B-cell memory cells and effector vector cells and see how long those effector vector cells can be active in protection? Those are studies that are ongoing now.”

Dr. Maldonado disclosed that she is a member of the data safety monitoring board for a non–COVID-19 vaccine being developed by Pfizer.

[email protected]

If everything goes as planned, the Pfizer and Moderna mRNA COVID-19 vaccines could be granted emergency use authorization (EUA) for children aged 12 years and older by the fall of 2021.

Courtesy Dr. Maldonado

According to Yvonne Maldonado, MD, Pfizer has fully enrolled adolescent trials and Moderna is currently enrolling 3,000 adolescents in a safety and reactogenicity trial known as TeenCOVE, in which participants will receive an intramuscular injection of 100 mcg mRNA-1273 on day 1 and on day 29. Meanwhile, Johnson & Johnson and AstraZeneca will be starting to enroll older children and adolescents into studies within the next several weeks.

The companies are also planning to enroll younger children, Dr. Maldonado, the Taube professor of global health and infectious diseases at Stanford (Calif.) University, said during the Society for Pediatric Dermatology pre-AAD meeting. “At least two of the vaccine companies have indicated that they would like to start enrolling children as young as 2-5 years of age and eventually getting down to infants and toddlers if the vaccines prove to be safe and effective in the older children. Eventually, we hope to get to the level where we can have several vaccine candidates for all children 6 months of age and older.”

In the future, she said, infectious disease experts hope to see antiviral, immunomodulatory, anti-inflammatory, and monoclonal therapies for all populations including children, although trials in this population have not begun. “Clinical trials must be flexible and adaptive to deal with children and adolescents,” added Dr. Maldonado, who is also senior associate dean for faculty development and diversity at Stanford.

“We would ideally like to have new correlates of protection, as well as biomarkers to follow for evidence of effectiveness. We also would love to see vaccines in the pediatric population as soon as possible, because herd immunity is the ultimate goal for protection against this disease and prevention of additional transmission over time.” However, she said, the degree and durability of immunity has yet to be determined, and vaccine-associated immune effects are unknown. In the meantime, infectious disease researchers expect nonpharmacologic interventions, such as wearing face masks and social distancing to continue for an undefined period.

(Less than 2 weeks after Dr. Maldonado spoke at the SPD meeting, Pfizer announced in a press release that, in phase 3 clinical trials, the company’s coronavirus vaccine was 100% effective in protecting children aged 12-15 years from infection, with a “robust” antibody responses and side effects similar to those experienced by those aged 16-25 years. The company also announced that it plans to seek Food and Drug Administration EUA for this age group. Asked to comment on this update, Dr. Maldonado said the results released by Pfizer “suggest that their COVID-19 vaccine is very safe and highly effective in preventing COVID-19 among children 12-15 years of age.” She added that additional data from the Pfizer trials as well as from Moderna and Johnson & Johnson vaccine trials “will hopefully lead to FDA EUA review in the coming weeks,” and that COVID-19 vaccinations for children “may be possible by this summer.”)
 

_{Children with underlying diseases or on immune suppressants}

At the SPD meeting, an attendee asked if there were any pediatric patients for whom she would not recommend receiving a COVID-19 vaccine because of an underlying disease or concurrent therapy with immune suppressants. “We don’t have those data yet,” Dr. Maldonado said. “Based on what we’re seeing with adults, it does appear that those with underlying conditions are at somewhat higher risk of developing severe infection and may therefore most likely to need vaccination. Most of those risks are cardiovascular, obesity, and other factors, but not necessarily immunocompromising conditions. More likely what we’re seeing is that people with underlying immunocompromising conditions may not mount a good response to the vaccines at this time. It doesn’t mean we shouldn’t give the vaccines, but we need to learn more about that.”

Dr. Maldonado went on to note that, as vaccine manufacturers commence pediatric trials, healthy children will be tested first, followed in due time with children who have immunocompromised conditions. “The question will be whether or not we should give monoclonal antibodies to those particular children to help boost their immunity to SARS-CoV-2, because they might not have a good response to the vaccines,” she said. “Those things need to be sorted out, but there’s no safety signal or concerns at this point for vaccine to be given to immunocompromised individuals.”

Another meeting attendee asked Dr. Maldonado if she thinks there is a practical role for assessing markers of T-cell immunity when evaluating suspected COVID-19 patients who may test negative on serology, Dr. Maldonado said that she and her colleagues are seeking pediatric patients who were treated for COVID-19 at Stanford, in an effort to sort this out.

They are checking peripheral blood mononuclear cells in these patients “to try and tease out what the immune response is in kids who have serious disease, versus those who came in with acute disease, versus those who are asymptomatic,” and comparing them with children who don’t have infection, she explained. “The question is, what is the role of T cells and how much do they contribute? One of the biggest questions we have is, do we have an immune correlate? Can we detect a particular level of neutralizing antibody that seems to be protective? If so, how long is it protective, and can we look for T- and B-cell memory cells and effector vector cells and see how long those effector vector cells can be active in protection? Those are studies that are ongoing now.”

Dr. Maldonado disclosed that she is a member of the data safety monitoring board for a non–COVID-19 vaccine being developed by Pfizer.

[email protected]

If everything goes as planned, the Pfizer and Moderna mRNA COVID-19 vaccines could be granted emergency use authorization (EUA) for children aged 12 years and older by the fall of 2021.

Courtesy Dr. Maldonado

According to Yvonne Maldonado, MD, Pfizer has fully enrolled adolescent trials and Moderna is currently enrolling 3,000 adolescents in a safety and reactogenicity trial known as TeenCOVE, in which participants will receive an intramuscular injection of 100 mcg mRNA-1273 on day 1 and on day 29. Meanwhile, Johnson & Johnson and AstraZeneca will be starting to enroll older children and adolescents into studies within the next several weeks.

The companies are also planning to enroll younger children, Dr. Maldonado, the Taube professor of global health and infectious diseases at Stanford (Calif.) University, said during the Society for Pediatric Dermatology pre-AAD meeting. “At least two of the vaccine companies have indicated that they would like to start enrolling children as young as 2-5 years of age and eventually getting down to infants and toddlers if the vaccines prove to be safe and effective in the older children. Eventually, we hope to get to the level where we can have several vaccine candidates for all children 6 months of age and older.”

In the future, she said, infectious disease experts hope to see antiviral, immunomodulatory, anti-inflammatory, and monoclonal therapies for all populations including children, although trials in this population have not begun. “Clinical trials must be flexible and adaptive to deal with children and adolescents,” added Dr. Maldonado, who is also senior associate dean for faculty development and diversity at Stanford.

“We would ideally like to have new correlates of protection, as well as biomarkers to follow for evidence of effectiveness. We also would love to see vaccines in the pediatric population as soon as possible, because herd immunity is the ultimate goal for protection against this disease and prevention of additional transmission over time.” However, she said, the degree and durability of immunity has yet to be determined, and vaccine-associated immune effects are unknown. In the meantime, infectious disease researchers expect nonpharmacologic interventions, such as wearing face masks and social distancing to continue for an undefined period.

(Less than 2 weeks after Dr. Maldonado spoke at the SPD meeting, Pfizer announced in a press release that, in phase 3 clinical trials, the company’s coronavirus vaccine was 100% effective in protecting children aged 12-15 years from infection, with a “robust” antibody responses and side effects similar to those experienced by those aged 16-25 years. The company also announced that it plans to seek Food and Drug Administration EUA for this age group. Asked to comment on this update, Dr. Maldonado said the results released by Pfizer “suggest that their COVID-19 vaccine is very safe and highly effective in preventing COVID-19 among children 12-15 years of age.” She added that additional data from the Pfizer trials as well as from Moderna and Johnson & Johnson vaccine trials “will hopefully lead to FDA EUA review in the coming weeks,” and that COVID-19 vaccinations for children “may be possible by this summer.”)
 

_{Children with underlying diseases or on immune suppressants}

At the SPD meeting, an attendee asked if there were any pediatric patients for whom she would not recommend receiving a COVID-19 vaccine because of an underlying disease or concurrent therapy with immune suppressants. “We don’t have those data yet,” Dr. Maldonado said. “Based on what we’re seeing with adults, it does appear that those with underlying conditions are at somewhat higher risk of developing severe infection and may therefore most likely to need vaccination. Most of those risks are cardiovascular, obesity, and other factors, but not necessarily immunocompromising conditions. More likely what we’re seeing is that people with underlying immunocompromising conditions may not mount a good response to the vaccines at this time. It doesn’t mean we shouldn’t give the vaccines, but we need to learn more about that.”

Dr. Maldonado went on to note that, as vaccine manufacturers commence pediatric trials, healthy children will be tested first, followed in due time with children who have immunocompromised conditions. “The question will be whether or not we should give monoclonal antibodies to those particular children to help boost their immunity to SARS-CoV-2, because they might not have a good response to the vaccines,” she said. “Those things need to be sorted out, but there’s no safety signal or concerns at this point for vaccine to be given to immunocompromised individuals.”

Another meeting attendee asked Dr. Maldonado if she thinks there is a practical role for assessing markers of T-cell immunity when evaluating suspected COVID-19 patients who may test negative on serology, Dr. Maldonado said that she and her colleagues are seeking pediatric patients who were treated for COVID-19 at Stanford, in an effort to sort this out.

They are checking peripheral blood mononuclear cells in these patients “to try and tease out what the immune response is in kids who have serious disease, versus those who came in with acute disease, versus those who are asymptomatic,” and comparing them with children who don’t have infection, she explained. “The question is, what is the role of T cells and how much do they contribute? One of the biggest questions we have is, do we have an immune correlate? Can we detect a particular level of neutralizing antibody that seems to be protective? If so, how long is it protective, and can we look for T- and B-cell memory cells and effector vector cells and see how long those effector vector cells can be active in protection? Those are studies that are ongoing now.”

Dr. Maldonado disclosed that she is a member of the data safety monitoring board for a non–COVID-19 vaccine being developed by Pfizer.

[email protected]

After losing at arbitration, as well as in federal court and partially on appeal, Tenet Healthcare is refusing to comment on whether it will continue to battle two Detroit-area cardiologists whom the hospital corporation fired from leadership positions in 2018.

The cardiologists were awarded $10.6 million from an arbitrator, who found that Detroit Medical Center (DMC) and its parent, Tenet, retaliated against Amir Kaki, MD, and Mahir Elder, MD, when the doctors repeatedly reported concerns about patient safety and potential fraud.

belchonock/Thinkstock

From respected to reviled

Both Dr. Kaki and Dr. Elder were respected at DMC, according to court filings.

Dr. Kaki was recruited from Weill Cornell Medical College by a Detroit mayor because of his expertise in interventional cardiology. He had staff privileges at DMC beginning in 2012 and was a clinical associate professor and assistant program director of the interventional cardiology fellowship program at Wayne State University in Detroit. He became director of the cardiac catheterization services unit at the new DMC Heart Hospital at Harper-Hutzel Hospital in Detroit in 2014, and 4 years later was appointed director of the facility’s anticoagulation clinic. Dr. Kaki was nominated for and completed Tenet’s Leadership Academy.

Dr. Elder was a clinical professor and assistant fellowship director at Wayne State and was a clinical professor of medicine at Michigan State University. Beginning in 2008, he held directorships at DMC’s cardiac care unit, ambulatory services program, cardiac CT angiogram program, PERT program, and carotid stenting program. Dr. Elder was voted Teacher of the Year for 10 consecutive years by DMC cardiology fellows.

The two doctors aimed high when it came to quality of care and ethics, according to legal filings. Over the years, Dr. Kaki and Dr. Elder repeatedly reported what they considered to be egregious violations of patient safety and of Medicare and Medicaid fraud laws. The clinicians complained about unsterile surgical instruments and the removal of a stat laboratory from the cardiac catheterization unit, noting that the removal would cause delays that would endanger lives.

At peer review meetings, as well as with administrators, they flagged colleagues who they said were performing unnecessary or dangerous procedures solely to generate revenue. At least one doctor falsified records of such a procedure after a patient died, alleged Dr. Kaki and Dr. Elder.

Tenet hired outside attorneys in the fall of 2018, telling Dr. Kaki and Dr. Elder that the legal team would investigate their complaints. However, the investigation was a sham: Filings allege that the investigation was used instead to build a case against Dr. Kaki and Dr. Elder and that Tenet leadership used the inquiry to pressure the cardiologists to resign.

They refused, and in October 2018, they were fired from their leadership positions. DMC and Tenet then held a press conference in which they said that Dr. Kaki and Dr. Elder had been dismissed for “violations” of the “Tenet Standards of Conduct.”
 

Cardiologists push back

Dr. Kaki and Dr. Elder, however, were not willing to just walk away. They sought reinstatement through an internal DMC appeals panel of their peers. The clinicians who participated on that panel ruled that neither firing was justified.

But DMC’s governing board voted in April 2020 to deny privileges to both cardiologists.

Tenet continued a campaign of retaliation, according to legal filings, by not paying the clinicians for being on call, by removing them from peer review committees, and by prohibiting them from teaching or giving lectures. DMC refused to give Dr. Kaki his personnel record, stating that he was never an employee when he was in the leadership position. Dr. Kaki sued, and a Wayne County Circuit Court judge granted his motion to get his file. DMC and Tenet appealed that ruling but lost.

Eventually, Ms. Gordon sued DMC and Tenet in federal court, alleging the hospital retaliated against the cardiologists, interfered with their ability to earn a living by disparaging them, refused to renew their privileges in 2019, and committed violations under multiple federal and state statutes, including the False Claims Act and the Fair Labor Standards Act.

Tenet successfully argued that the case should go to arbitration.

Arbitrator Mary Beth Kelly, though, ruled in December 2020 that the vast majority of the complaints compiled against the two physicians in the external investigation were not verified or supported and that Tenet and DMC had retaliated against Dr. Kaki and Dr. Elder.

For that harm, Ms. Kelly awarded each clinician $1 million, according to the final ruling shared in an interview.

In addition, she awarded Dr. Kaki $2.3 million in back pay and 2 years of front pay (slightly more than $1 million). She awarded Dr. Elder $2.3 million in back pay and $2.1 million in front pay for 4 years, noting that “his strong association with DMC may make it more difficult for him to successfully transition into the situation he enjoyed prior to termination and nonrenewal.”

The clinicians also were awarded legal fees of $623,816 and court costs of $110,673.
 

“Wholesale retrial”

To secure the award, Ms. Gordon had to seek a ruling from the U.S. District Court for Eastern Michigan. Tenet asked that court to overturn the arbitrator’s award and to keep it sealed from public view.

In his February ruling, Judge Arthur J. Tarnow wrote that Tenet and DMC “not only attempt to relitigate the legal issues, but also endeavor to introduce a factual counternarrative unmoored from the findings of the Arbitrator and including evidence which the Arbitrator specifically found inadmissible.

“By seeking a wholesale retrial of their case after forcing plaintiffs to arbitrate in the first place,” Tenet and DMC basically ignored the goal of arbitration, which is to relieve judicial congestion and provide a faster and cheaper alternative to litigation, he wrote.

Judge Tarnow also warned Tenet and DMC against taking too long to reinstate privileges for Dr. Kaki and Dr. Elder. If they “continue to delay the restoration of plaintiffs’ privileges in the hopes of a different result on appeal, they will be in violation of this Order,” said the judge.

Tenet, however, tried one more avenue to block the cardiologists from getting privileges, appealing to the Sixth Circuit, which again ordered the company to grant the 1-year privileges.

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

After losing at arbitration, as well as in federal court and partially on appeal, Tenet Healthcare is refusing to comment on whether it will continue to battle two Detroit-area cardiologists whom the hospital corporation fired from leadership positions in 2018.

The cardiologists were awarded $10.6 million from an arbitrator, who found that Detroit Medical Center (DMC) and its parent, Tenet, retaliated against Amir Kaki, MD, and Mahir Elder, MD, when the doctors repeatedly reported concerns about patient safety and potential fraud.

belchonock/Thinkstock

From respected to reviled

Both Dr. Kaki and Dr. Elder were respected at DMC, according to court filings.

Dr. Kaki was recruited from Weill Cornell Medical College by a Detroit mayor because of his expertise in interventional cardiology. He had staff privileges at DMC beginning in 2012 and was a clinical associate professor and assistant program director of the interventional cardiology fellowship program at Wayne State University in Detroit. He became director of the cardiac catheterization services unit at the new DMC Heart Hospital at Harper-Hutzel Hospital in Detroit in 2014, and 4 years later was appointed director of the facility’s anticoagulation clinic. Dr. Kaki was nominated for and completed Tenet’s Leadership Academy.

Dr. Elder was a clinical professor and assistant fellowship director at Wayne State and was a clinical professor of medicine at Michigan State University. Beginning in 2008, he held directorships at DMC’s cardiac care unit, ambulatory services program, cardiac CT angiogram program, PERT program, and carotid stenting program. Dr. Elder was voted Teacher of the Year for 10 consecutive years by DMC cardiology fellows.

The two doctors aimed high when it came to quality of care and ethics, according to legal filings. Over the years, Dr. Kaki and Dr. Elder repeatedly reported what they considered to be egregious violations of patient safety and of Medicare and Medicaid fraud laws. The clinicians complained about unsterile surgical instruments and the removal of a stat laboratory from the cardiac catheterization unit, noting that the removal would cause delays that would endanger lives.

At peer review meetings, as well as with administrators, they flagged colleagues who they said were performing unnecessary or dangerous procedures solely to generate revenue. At least one doctor falsified records of such a procedure after a patient died, alleged Dr. Kaki and Dr. Elder.

Tenet hired outside attorneys in the fall of 2018, telling Dr. Kaki and Dr. Elder that the legal team would investigate their complaints. However, the investigation was a sham: Filings allege that the investigation was used instead to build a case against Dr. Kaki and Dr. Elder and that Tenet leadership used the inquiry to pressure the cardiologists to resign.

They refused, and in October 2018, they were fired from their leadership positions. DMC and Tenet then held a press conference in which they said that Dr. Kaki and Dr. Elder had been dismissed for “violations” of the “Tenet Standards of Conduct.”
 

Cardiologists push back

Dr. Kaki and Dr. Elder, however, were not willing to just walk away. They sought reinstatement through an internal DMC appeals panel of their peers. The clinicians who participated on that panel ruled that neither firing was justified.

But DMC’s governing board voted in April 2020 to deny privileges to both cardiologists.

Tenet continued a campaign of retaliation, according to legal filings, by not paying the clinicians for being on call, by removing them from peer review committees, and by prohibiting them from teaching or giving lectures. DMC refused to give Dr. Kaki his personnel record, stating that he was never an employee when he was in the leadership position. Dr. Kaki sued, and a Wayne County Circuit Court judge granted his motion to get his file. DMC and Tenet appealed that ruling but lost.

Eventually, Ms. Gordon sued DMC and Tenet in federal court, alleging the hospital retaliated against the cardiologists, interfered with their ability to earn a living by disparaging them, refused to renew their privileges in 2019, and committed violations under multiple federal and state statutes, including the False Claims Act and the Fair Labor Standards Act.

Tenet successfully argued that the case should go to arbitration.

Arbitrator Mary Beth Kelly, though, ruled in December 2020 that the vast majority of the complaints compiled against the two physicians in the external investigation were not verified or supported and that Tenet and DMC had retaliated against Dr. Kaki and Dr. Elder.

For that harm, Ms. Kelly awarded each clinician $1 million, according to the final ruling shared in an interview.

In addition, she awarded Dr. Kaki $2.3 million in back pay and 2 years of front pay (slightly more than $1 million). She awarded Dr. Elder $2.3 million in back pay and $2.1 million in front pay for 4 years, noting that “his strong association with DMC may make it more difficult for him to successfully transition into the situation he enjoyed prior to termination and nonrenewal.”

The clinicians also were awarded legal fees of $623,816 and court costs of $110,673.
 

“Wholesale retrial”

To secure the award, Ms. Gordon had to seek a ruling from the U.S. District Court for Eastern Michigan. Tenet asked that court to overturn the arbitrator’s award and to keep it sealed from public view.

In his February ruling, Judge Arthur J. Tarnow wrote that Tenet and DMC “not only attempt to relitigate the legal issues, but also endeavor to introduce a factual counternarrative unmoored from the findings of the Arbitrator and including evidence which the Arbitrator specifically found inadmissible.

“By seeking a wholesale retrial of their case after forcing plaintiffs to arbitrate in the first place,” Tenet and DMC basically ignored the goal of arbitration, which is to relieve judicial congestion and provide a faster and cheaper alternative to litigation, he wrote.

Judge Tarnow also warned Tenet and DMC against taking too long to reinstate privileges for Dr. Kaki and Dr. Elder. If they “continue to delay the restoration of plaintiffs’ privileges in the hopes of a different result on appeal, they will be in violation of this Order,” said the judge.

Tenet, however, tried one more avenue to block the cardiologists from getting privileges, appealing to the Sixth Circuit, which again ordered the company to grant the 1-year privileges.

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

After losing at arbitration, as well as in federal court and partially on appeal, Tenet Healthcare is refusing to comment on whether it will continue to battle two Detroit-area cardiologists whom the hospital corporation fired from leadership positions in 2018.

The cardiologists were awarded $10.6 million from an arbitrator, who found that Detroit Medical Center (DMC) and its parent, Tenet, retaliated against Amir Kaki, MD, and Mahir Elder, MD, when the doctors repeatedly reported concerns about patient safety and potential fraud.

belchonock/Thinkstock

From respected to reviled

Both Dr. Kaki and Dr. Elder were respected at DMC, according to court filings.

Dr. Kaki was recruited from Weill Cornell Medical College by a Detroit mayor because of his expertise in interventional cardiology. He had staff privileges at DMC beginning in 2012 and was a clinical associate professor and assistant program director of the interventional cardiology fellowship program at Wayne State University in Detroit. He became director of the cardiac catheterization services unit at the new DMC Heart Hospital at Harper-Hutzel Hospital in Detroit in 2014, and 4 years later was appointed director of the facility’s anticoagulation clinic. Dr. Kaki was nominated for and completed Tenet’s Leadership Academy.

Dr. Elder was a clinical professor and assistant fellowship director at Wayne State and was a clinical professor of medicine at Michigan State University. Beginning in 2008, he held directorships at DMC’s cardiac care unit, ambulatory services program, cardiac CT angiogram program, PERT program, and carotid stenting program. Dr. Elder was voted Teacher of the Year for 10 consecutive years by DMC cardiology fellows.

The two doctors aimed high when it came to quality of care and ethics, according to legal filings. Over the years, Dr. Kaki and Dr. Elder repeatedly reported what they considered to be egregious violations of patient safety and of Medicare and Medicaid fraud laws. The clinicians complained about unsterile surgical instruments and the removal of a stat laboratory from the cardiac catheterization unit, noting that the removal would cause delays that would endanger lives.

At peer review meetings, as well as with administrators, they flagged colleagues who they said were performing unnecessary or dangerous procedures solely to generate revenue. At least one doctor falsified records of such a procedure after a patient died, alleged Dr. Kaki and Dr. Elder.

Tenet hired outside attorneys in the fall of 2018, telling Dr. Kaki and Dr. Elder that the legal team would investigate their complaints. However, the investigation was a sham: Filings allege that the investigation was used instead to build a case against Dr. Kaki and Dr. Elder and that Tenet leadership used the inquiry to pressure the cardiologists to resign.

They refused, and in October 2018, they were fired from their leadership positions. DMC and Tenet then held a press conference in which they said that Dr. Kaki and Dr. Elder had been dismissed for “violations” of the “Tenet Standards of Conduct.”
 

Cardiologists push back

Dr. Kaki and Dr. Elder, however, were not willing to just walk away. They sought reinstatement through an internal DMC appeals panel of their peers. The clinicians who participated on that panel ruled that neither firing was justified.

But DMC’s governing board voted in April 2020 to deny privileges to both cardiologists.

Tenet continued a campaign of retaliation, according to legal filings, by not paying the clinicians for being on call, by removing them from peer review committees, and by prohibiting them from teaching or giving lectures. DMC refused to give Dr. Kaki his personnel record, stating that he was never an employee when he was in the leadership position. Dr. Kaki sued, and a Wayne County Circuit Court judge granted his motion to get his file. DMC and Tenet appealed that ruling but lost.

Eventually, Ms. Gordon sued DMC and Tenet in federal court, alleging the hospital retaliated against the cardiologists, interfered with their ability to earn a living by disparaging them, refused to renew their privileges in 2019, and committed violations under multiple federal and state statutes, including the False Claims Act and the Fair Labor Standards Act.

Tenet successfully argued that the case should go to arbitration.

Arbitrator Mary Beth Kelly, though, ruled in December 2020 that the vast majority of the complaints compiled against the two physicians in the external investigation were not verified or supported and that Tenet and DMC had retaliated against Dr. Kaki and Dr. Elder.

For that harm, Ms. Kelly awarded each clinician $1 million, according to the final ruling shared in an interview.

In addition, she awarded Dr. Kaki $2.3 million in back pay and 2 years of front pay (slightly more than $1 million). She awarded Dr. Elder $2.3 million in back pay and $2.1 million in front pay for 4 years, noting that “his strong association with DMC may make it more difficult for him to successfully transition into the situation he enjoyed prior to termination and nonrenewal.”

The clinicians also were awarded legal fees of $623,816 and court costs of $110,673.
 

“Wholesale retrial”

To secure the award, Ms. Gordon had to seek a ruling from the U.S. District Court for Eastern Michigan. Tenet asked that court to overturn the arbitrator’s award and to keep it sealed from public view.

In his February ruling, Judge Arthur J. Tarnow wrote that Tenet and DMC “not only attempt to relitigate the legal issues, but also endeavor to introduce a factual counternarrative unmoored from the findings of the Arbitrator and including evidence which the Arbitrator specifically found inadmissible.

“By seeking a wholesale retrial of their case after forcing plaintiffs to arbitrate in the first place,” Tenet and DMC basically ignored the goal of arbitration, which is to relieve judicial congestion and provide a faster and cheaper alternative to litigation, he wrote.

Judge Tarnow also warned Tenet and DMC against taking too long to reinstate privileges for Dr. Kaki and Dr. Elder. If they “continue to delay the restoration of plaintiffs’ privileges in the hopes of a different result on appeal, they will be in violation of this Order,” said the judge.

Tenet, however, tried one more avenue to block the cardiologists from getting privileges, appealing to the Sixth Circuit, which again ordered the company to grant the 1-year privileges.

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

One of the top publications in gastroenterology in 2020 was a Dutch study demonstrating that a computer-aided system suitable for real-time use in clinical practice detected early neoplasia in patients with Barrett’s esophagus with impressively greater accuracy than did a group of general endoscopists, according to Douglas A. Corley, MD, PhD.

It’s not just his personal opinion that this was one of the major studies of the past year, either. Analytic tools showed the Dutch report was one of the most frequently downloaded studies in 2020 by both clinical gastroenterologists and researchers, said Dr. Corley, director of delivery science and applied research at Kaiser Permanente of Northern California, Oakland, and a faculty gastroenterologist at the University of California, San Francisco.

The deep-learning system developed, evaluated, and externally validated by the Dutch investigators is designed to reduce the rate of failed detection of high-grade dysplasia and early adenocarcinoma in patients undergoing surveillance by general practice gastrointestinal endoscopists. The false-negative rate in looking for the sometimes subtle mucosal surface abnormalities indicative of early neoplasia is known to be higher among these general endoscopists than that among expert endoscopists, and yet it’s the general endoscopists who perform the majority of cancer surveillance in patients with Barrett’s esophagus.

The Dutch group developed the computer-aided detection system by applying artificial intelligence methods to analyze nearly one half-million endoscopic images of confirmed early neoplasia. Once the system was ready to go, they compared its diagnostic accuracy in 80 patients to that of 53 general, nonexpert endoscopists. The deep-learning system had 93% sensitivity and 83% specificity for identification of early neoplasia, significantly better than the 72% sensitivity and 74% specificity for the general endoscopists. The overall accuracy of the computer-assisted detection system was 88%, compared to 73% for the general endoscopists. Moreover, the deep-learning system achieved greater accuracy than did any single one of the endoscopists.

“I think this will be a really helpful addition, the equivalent of a second endoscopist raising a yellow flag to take a closer look at a particular area. It’ll be complementary,” Dr. Corley said at the Gastroenterology Updates, IBD, Liver Disease Conference.

An audience member said he’s aware that other computer-assisted detection systems have also shown outstanding performance for the detection of early neoplasia in Barrett’s esophagus. He asked, why aren’t these being deployed yet in routine clinical practice?

Two reasons, Dr. Corley replied. One is that some of those systems aren’t capable of working during real-time endoscopy. Also, industry seems to be taking a wait-and-see approach. The field of applied artificial intelligence is moving incredibly rapidly, and none of the endoscopic equipment manufacturers wants to incorporate a computer-assisted detection system into their gear when rumor has it that an even better system is going to be announced 6 months later. The manufacturers want to make sure they’re operationalizing the right one.

He suspects the major players in the endoscopic imaging industry are waiting to find a computer-assisted detection system that’s been published and widely accepted as clearly a winner. Then they’ll introduce it into their equipment.

“I do think we’re probably going to be seeing these increasingly. Some computer-assisted detection systems for colon cancer are starting to be put into equipment,” he observed.

Dr. Corley reported having no financial conflicts regarding his presentation.

Help your patients better understand the risks, testing, and treatment options for Barrett’s esophagus by sharing education from the AGA GI Patient Center: www.gastro.org/BE.

[email protected]

One of the top publications in gastroenterology in 2020 was a Dutch study demonstrating that a computer-aided system suitable for real-time use in clinical practice detected early neoplasia in patients with Barrett’s esophagus with impressively greater accuracy than did a group of general endoscopists, according to Douglas A. Corley, MD, PhD.

It’s not just his personal opinion that this was one of the major studies of the past year, either. Analytic tools showed the Dutch report was one of the most frequently downloaded studies in 2020 by both clinical gastroenterologists and researchers, said Dr. Corley, director of delivery science and applied research at Kaiser Permanente of Northern California, Oakland, and a faculty gastroenterologist at the University of California, San Francisco.

The deep-learning system developed, evaluated, and externally validated by the Dutch investigators is designed to reduce the rate of failed detection of high-grade dysplasia and early adenocarcinoma in patients undergoing surveillance by general practice gastrointestinal endoscopists. The false-negative rate in looking for the sometimes subtle mucosal surface abnormalities indicative of early neoplasia is known to be higher among these general endoscopists than that among expert endoscopists, and yet it’s the general endoscopists who perform the majority of cancer surveillance in patients with Barrett’s esophagus.

The Dutch group developed the computer-aided detection system by applying artificial intelligence methods to analyze nearly one half-million endoscopic images of confirmed early neoplasia. Once the system was ready to go, they compared its diagnostic accuracy in 80 patients to that of 53 general, nonexpert endoscopists. The deep-learning system had 93% sensitivity and 83% specificity for identification of early neoplasia, significantly better than the 72% sensitivity and 74% specificity for the general endoscopists. The overall accuracy of the computer-assisted detection system was 88%, compared to 73% for the general endoscopists. Moreover, the deep-learning system achieved greater accuracy than did any single one of the endoscopists.

“I think this will be a really helpful addition, the equivalent of a second endoscopist raising a yellow flag to take a closer look at a particular area. It’ll be complementary,” Dr. Corley said at the Gastroenterology Updates, IBD, Liver Disease Conference.

An audience member said he’s aware that other computer-assisted detection systems have also shown outstanding performance for the detection of early neoplasia in Barrett’s esophagus. He asked, why aren’t these being deployed yet in routine clinical practice?

Two reasons, Dr. Corley replied. One is that some of those systems aren’t capable of working during real-time endoscopy. Also, industry seems to be taking a wait-and-see approach. The field of applied artificial intelligence is moving incredibly rapidly, and none of the endoscopic equipment manufacturers wants to incorporate a computer-assisted detection system into their gear when rumor has it that an even better system is going to be announced 6 months later. The manufacturers want to make sure they’re operationalizing the right one.

He suspects the major players in the endoscopic imaging industry are waiting to find a computer-assisted detection system that’s been published and widely accepted as clearly a winner. Then they’ll introduce it into their equipment.

“I do think we’re probably going to be seeing these increasingly. Some computer-assisted detection systems for colon cancer are starting to be put into equipment,” he observed.

Dr. Corley reported having no financial conflicts regarding his presentation.

Help your patients better understand the risks, testing, and treatment options for Barrett’s esophagus by sharing education from the AGA GI Patient Center: www.gastro.org/BE.

[email protected]

One of the top publications in gastroenterology in 2020 was a Dutch study demonstrating that a computer-aided system suitable for real-time use in clinical practice detected early neoplasia in patients with Barrett’s esophagus with impressively greater accuracy than did a group of general endoscopists, according to Douglas A. Corley, MD, PhD.

It’s not just his personal opinion that this was one of the major studies of the past year, either. Analytic tools showed the Dutch report was one of the most frequently downloaded studies in 2020 by both clinical gastroenterologists and researchers, said Dr. Corley, director of delivery science and applied research at Kaiser Permanente of Northern California, Oakland, and a faculty gastroenterologist at the University of California, San Francisco.

The deep-learning system developed, evaluated, and externally validated by the Dutch investigators is designed to reduce the rate of failed detection of high-grade dysplasia and early adenocarcinoma in patients undergoing surveillance by general practice gastrointestinal endoscopists. The false-negative rate in looking for the sometimes subtle mucosal surface abnormalities indicative of early neoplasia is known to be higher among these general endoscopists than that among expert endoscopists, and yet it’s the general endoscopists who perform the majority of cancer surveillance in patients with Barrett’s esophagus.

The Dutch group developed the computer-aided detection system by applying artificial intelligence methods to analyze nearly one half-million endoscopic images of confirmed early neoplasia. Once the system was ready to go, they compared its diagnostic accuracy in 80 patients to that of 53 general, nonexpert endoscopists. The deep-learning system had 93% sensitivity and 83% specificity for identification of early neoplasia, significantly better than the 72% sensitivity and 74% specificity for the general endoscopists. The overall accuracy of the computer-assisted detection system was 88%, compared to 73% for the general endoscopists. Moreover, the deep-learning system achieved greater accuracy than did any single one of the endoscopists.

“I think this will be a really helpful addition, the equivalent of a second endoscopist raising a yellow flag to take a closer look at a particular area. It’ll be complementary,” Dr. Corley said at the Gastroenterology Updates, IBD, Liver Disease Conference.

An audience member said he’s aware that other computer-assisted detection systems have also shown outstanding performance for the detection of early neoplasia in Barrett’s esophagus. He asked, why aren’t these being deployed yet in routine clinical practice?

Two reasons, Dr. Corley replied. One is that some of those systems aren’t capable of working during real-time endoscopy. Also, industry seems to be taking a wait-and-see approach. The field of applied artificial intelligence is moving incredibly rapidly, and none of the endoscopic equipment manufacturers wants to incorporate a computer-assisted detection system into their gear when rumor has it that an even better system is going to be announced 6 months later. The manufacturers want to make sure they’re operationalizing the right one.

He suspects the major players in the endoscopic imaging industry are waiting to find a computer-assisted detection system that’s been published and widely accepted as clearly a winner. Then they’ll introduce it into their equipment.

“I do think we’re probably going to be seeing these increasingly. Some computer-assisted detection systems for colon cancer are starting to be put into equipment,” he observed.

Dr. Corley reported having no financial conflicts regarding his presentation.

Help your patients better understand the risks, testing, and treatment options for Barrett’s esophagus by sharing education from the AGA GI Patient Center: www.gastro.org/BE.

[email protected]

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. 

April is National Autism Awareness Month, and April 2 is World Autism Awareness Day. In the United States, there appears to be a heightened level of awareness of this condition over the past 10-15 years that has helped reduced its stigma, improve early identification, and (most importantly) increase access to early interventions for children and families.

The most recent prevalence estimates of autism in children in the United States is 1 in 54. This is a 10% increase since 2014 (1 in 59). Those most recent Centers for Disease Control and Prevention surveillance reports also point to a reduction in the racial gap between Black and White children when it comes to diagnosis.¹ Across the globe, there are more than 100 autism societies, and research designed to improve prevalence data in lower- to middle-income countries has also increased.²

Even with these recent encouraging numbers regarding identification of autism in historically underrepresented groups in the United States, there are still differences among those groups, compared with children who are socioeconomically well-off, White, or live in large urban areas.³ Specifically, Latinx children were documented to be identified with autism at lower rates, compared with Whites and Blacks. In addition, Black and Latinx children are still diagnosed at a later age, compared with White children. This is important to note because historically, Black and Latinx children have been diagnosed with severe forms of autism or co-occurring intellectual disability at a higher rate, compared with their White counterparts.⁴ Thus, it would not be inappropriate to infer that Black and Latinx children with “milder” presenting autism symptoms or without co-occurring ID are not identified at the same rates, compared with their White peers. Furthermore, when peering into the international data, epidemiologic studies regarding prevalence, clinical course, and outcomes is skewed heavily toward a few Western industrialized nations, Japan, and South Korea.⁵

In all, when observing Autism Awareness Month, we should continue to recognize that these aforementioned epidemiologic disparities still exist – both locally and globally. The global COVID-19 pandemic has almost certainly worsened these disparities because both clinical and research work have consequences that are not yet fully known. As long as these trends remain, racial and socioeconomic differences in access to treatment in the United States will remain. From an international perspective, we may never appreciate the true extent of the cultural variability within autism symptoms and so may never appreciate the full spectrum of ways the condition can present.
 

References

1. MMWR Surveill Summ. 2020 Mar 27;69(4):1-12. Erratum in: MMWR Morb Mortal Wkly Rep. 2020 Apr 24;69(16):503.

2. Lancet Glob Health. 2018 Oct;6(10):e1100-21.

3. Am J Public Health. 2009;99(3):493-8.

4. J Dev Behav Pediatr. 2011 Apr;32(3):179-87 and MMWR Surveill Summ. 2019;68(2):1-19.

5. Brain Sci. 2020;10(5):274. doi: 10.3390/brainsci10050274.
 

Dr. Emejuru is a child and adolescent psychiatrist with Community Hospital of Monterey Peninsula (CHOMP) and its Ohana Center for Child and Adolescent Behavioral Health in Monterey, Calif. His expertise is specific to conducting evaluations for autism spectrum disorder and evaluating, diagnosing, and treating co-occurring psychiatric disorders after training at the Johns Hopkins Hospital/Kennedy Krieger Institute’s Center for Autism and Related Disorders in Baltimore. He has no conflicts of interest.

April is National Autism Awareness Month, and April 2 is World Autism Awareness Day. In the United States, there appears to be a heightened level of awareness of this condition over the past 10-15 years that has helped reduced its stigma, improve early identification, and (most importantly) increase access to early interventions for children and families.

The most recent prevalence estimates of autism in children in the United States is 1 in 54. This is a 10% increase since 2014 (1 in 59). Those most recent Centers for Disease Control and Prevention surveillance reports also point to a reduction in the racial gap between Black and White children when it comes to diagnosis.¹ Across the globe, there are more than 100 autism societies, and research designed to improve prevalence data in lower- to middle-income countries has also increased.²

Even with these recent encouraging numbers regarding identification of autism in historically underrepresented groups in the United States, there are still differences among those groups, compared with children who are socioeconomically well-off, White, or live in large urban areas.³ Specifically, Latinx children were documented to be identified with autism at lower rates, compared with Whites and Blacks. In addition, Black and Latinx children are still diagnosed at a later age, compared with White children. This is important to note because historically, Black and Latinx children have been diagnosed with severe forms of autism or co-occurring intellectual disability at a higher rate, compared with their White counterparts.⁴ Thus, it would not be inappropriate to infer that Black and Latinx children with “milder” presenting autism symptoms or without co-occurring ID are not identified at the same rates, compared with their White peers. Furthermore, when peering into the international data, epidemiologic studies regarding prevalence, clinical course, and outcomes is skewed heavily toward a few Western industrialized nations, Japan, and South Korea.⁵

In all, when observing Autism Awareness Month, we should continue to recognize that these aforementioned epidemiologic disparities still exist – both locally and globally. The global COVID-19 pandemic has almost certainly worsened these disparities because both clinical and research work have consequences that are not yet fully known. As long as these trends remain, racial and socioeconomic differences in access to treatment in the United States will remain. From an international perspective, we may never appreciate the true extent of the cultural variability within autism symptoms and so may never appreciate the full spectrum of ways the condition can present.
 

References

1. MMWR Surveill Summ. 2020 Mar 27;69(4):1-12. Erratum in: MMWR Morb Mortal Wkly Rep. 2020 Apr 24;69(16):503.

2. Lancet Glob Health. 2018 Oct;6(10):e1100-21.

3. Am J Public Health. 2009;99(3):493-8.

4. J Dev Behav Pediatr. 2011 Apr;32(3):179-87 and MMWR Surveill Summ. 2019;68(2):1-19.

5. Brain Sci. 2020;10(5):274. doi: 10.3390/brainsci10050274.
 

Dr. Emejuru is a child and adolescent psychiatrist with Community Hospital of Monterey Peninsula (CHOMP) and its Ohana Center for Child and Adolescent Behavioral Health in Monterey, Calif. His expertise is specific to conducting evaluations for autism spectrum disorder and evaluating, diagnosing, and treating co-occurring psychiatric disorders after training at the Johns Hopkins Hospital/Kennedy Krieger Institute’s Center for Autism and Related Disorders in Baltimore. He has no conflicts of interest.

April is National Autism Awareness Month, and April 2 is World Autism Awareness Day. In the United States, there appears to be a heightened level of awareness of this condition over the past 10-15 years that has helped reduced its stigma, improve early identification, and (most importantly) increase access to early interventions for children and families.

The most recent prevalence estimates of autism in children in the United States is 1 in 54. This is a 10% increase since 2014 (1 in 59). Those most recent Centers for Disease Control and Prevention surveillance reports also point to a reduction in the racial gap between Black and White children when it comes to diagnosis.¹ Across the globe, there are more than 100 autism societies, and research designed to improve prevalence data in lower- to middle-income countries has also increased.²

Even with these recent encouraging numbers regarding identification of autism in historically underrepresented groups in the United States, there are still differences among those groups, compared with children who are socioeconomically well-off, White, or live in large urban areas.³ Specifically, Latinx children were documented to be identified with autism at lower rates, compared with Whites and Blacks. In addition, Black and Latinx children are still diagnosed at a later age, compared with White children. This is important to note because historically, Black and Latinx children have been diagnosed with severe forms of autism or co-occurring intellectual disability at a higher rate, compared with their White counterparts.⁴ Thus, it would not be inappropriate to infer that Black and Latinx children with “milder” presenting autism symptoms or without co-occurring ID are not identified at the same rates, compared with their White peers. Furthermore, when peering into the international data, epidemiologic studies regarding prevalence, clinical course, and outcomes is skewed heavily toward a few Western industrialized nations, Japan, and South Korea.⁵

In all, when observing Autism Awareness Month, we should continue to recognize that these aforementioned epidemiologic disparities still exist – both locally and globally. The global COVID-19 pandemic has almost certainly worsened these disparities because both clinical and research work have consequences that are not yet fully known. As long as these trends remain, racial and socioeconomic differences in access to treatment in the United States will remain. From an international perspective, we may never appreciate the true extent of the cultural variability within autism symptoms and so may never appreciate the full spectrum of ways the condition can present.
 

References

1. MMWR Surveill Summ. 2020 Mar 27;69(4):1-12. Erratum in: MMWR Morb Mortal Wkly Rep. 2020 Apr 24;69(16):503.

2. Lancet Glob Health. 2018 Oct;6(10):e1100-21.

3. Am J Public Health. 2009;99(3):493-8.

4. J Dev Behav Pediatr. 2011 Apr;32(3):179-87 and MMWR Surveill Summ. 2019;68(2):1-19.

5. Brain Sci. 2020;10(5):274. doi: 10.3390/brainsci10050274.
 

Dr. Emejuru is a child and adolescent psychiatrist with Community Hospital of Monterey Peninsula (CHOMP) and its Ohana Center for Child and Adolescent Behavioral Health in Monterey, Calif. His expertise is specific to conducting evaluations for autism spectrum disorder and evaluating, diagnosing, and treating co-occurring psychiatric disorders after training at the Johns Hopkins Hospital/Kennedy Krieger Institute’s Center for Autism and Related Disorders in Baltimore. He has no conflicts of interest.

Treatment was attempted for both a suspected spider bite (2 weeks of topical triamcinolone 0.1%) and presumed cellulitis (oral doxycycline 100 mg bid/5 d), but neither improved her condition. Concerned for the possibility of cutaneous breast cancer, a punch biopsy was ordered and revealed diffuse dermal angiomatosis (DDA).

DDA is an uncommon proliferation of cutaneous blood vessels causing a reticular blood vessel pattern, as seen in this image. Typically, DDA is associated with tissue hypoxia due to arterial insufficiency from peripheral artery disease. In recent years, there have been numerous case reports of painful ulcerated lesions and reticular blood vessels occurring in women with large, pendulous breasts, increased body mass index, and a history of smoking. One theory suggests that the weight of the breasts causes tissue to stretch, compressing the blood vessels. This, combined with smoking, leads to localized hypoxia and DDA.

Treatments have included oral isotretinoin, calcium channel blockers, aspirin, or pentoxifylline to help circulation. Smoking cessation is recommended, as well as reduction mammoplasty to decrease the stretch on the tissues and relieve the local hypoxia. Although invasive, breast reduction surgery has moved to the forefront of therapy, with reports having shown resolution of the ulcers and pain.¹

Two important aspects of clinical medicine are highlighted by this case. First, nonhealing lesions that are not responding to prescribed therapies may require biopsy to rule out malignancy. Second, when there is difficulty making a diagnosis, especially with uncommon diseases, biopsy and input from a pathologist can be extremely helpful.

In this case, the patient was referred to Plastic Surgery and scheduled for reduction mammoplasty. The patient was advised to stop smoking for at least 4 weeks prior to the surgery to possibly improve her condition and reduce the likelihood of postoperative complications.

‌

Photo courtesy of Michael Louie, MD, and text courtesy of Michael Louie, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque

Treatment was attempted for both a suspected spider bite (2 weeks of topical triamcinolone 0.1%) and presumed cellulitis (oral doxycycline 100 mg bid/5 d), but neither improved her condition. Concerned for the possibility of cutaneous breast cancer, a punch biopsy was ordered and revealed diffuse dermal angiomatosis (DDA).

DDA is an uncommon proliferation of cutaneous blood vessels causing a reticular blood vessel pattern, as seen in this image. Typically, DDA is associated with tissue hypoxia due to arterial insufficiency from peripheral artery disease. In recent years, there have been numerous case reports of painful ulcerated lesions and reticular blood vessels occurring in women with large, pendulous breasts, increased body mass index, and a history of smoking. One theory suggests that the weight of the breasts causes tissue to stretch, compressing the blood vessels. This, combined with smoking, leads to localized hypoxia and DDA.

Treatments have included oral isotretinoin, calcium channel blockers, aspirin, or pentoxifylline to help circulation. Smoking cessation is recommended, as well as reduction mammoplasty to decrease the stretch on the tissues and relieve the local hypoxia. Although invasive, breast reduction surgery has moved to the forefront of therapy, with reports having shown resolution of the ulcers and pain.¹

Two important aspects of clinical medicine are highlighted by this case. First, nonhealing lesions that are not responding to prescribed therapies may require biopsy to rule out malignancy. Second, when there is difficulty making a diagnosis, especially with uncommon diseases, biopsy and input from a pathologist can be extremely helpful.

In this case, the patient was referred to Plastic Surgery and scheduled for reduction mammoplasty. The patient was advised to stop smoking for at least 4 weeks prior to the surgery to possibly improve her condition and reduce the likelihood of postoperative complications.

‌

Photo courtesy of Michael Louie, MD, and text courtesy of Michael Louie, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque

Treatment was attempted for both a suspected spider bite (2 weeks of topical triamcinolone 0.1%) and presumed cellulitis (oral doxycycline 100 mg bid/5 d), but neither improved her condition. Concerned for the possibility of cutaneous breast cancer, a punch biopsy was ordered and revealed diffuse dermal angiomatosis (DDA).

DDA is an uncommon proliferation of cutaneous blood vessels causing a reticular blood vessel pattern, as seen in this image. Typically, DDA is associated with tissue hypoxia due to arterial insufficiency from peripheral artery disease. In recent years, there have been numerous case reports of painful ulcerated lesions and reticular blood vessels occurring in women with large, pendulous breasts, increased body mass index, and a history of smoking. One theory suggests that the weight of the breasts causes tissue to stretch, compressing the blood vessels. This, combined with smoking, leads to localized hypoxia and DDA.

Treatments have included oral isotretinoin, calcium channel blockers, aspirin, or pentoxifylline to help circulation. Smoking cessation is recommended, as well as reduction mammoplasty to decrease the stretch on the tissues and relieve the local hypoxia. Although invasive, breast reduction surgery has moved to the forefront of therapy, with reports having shown resolution of the ulcers and pain.¹

Two important aspects of clinical medicine are highlighted by this case. First, nonhealing lesions that are not responding to prescribed therapies may require biopsy to rule out malignancy. Second, when there is difficulty making a diagnosis, especially with uncommon diseases, biopsy and input from a pathologist can be extremely helpful.

In this case, the patient was referred to Plastic Surgery and scheduled for reduction mammoplasty. The patient was advised to stop smoking for at least 4 weeks prior to the surgery to possibly improve her condition and reduce the likelihood of postoperative complications.

‌

Photo courtesy of Michael Louie, MD, and text courtesy of Michael Louie, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque

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.

Prior to the first approved disease modifying therapy (DMT) in the 1990s, treatment approaches for multiple sclerosis (MS) were not well understood. The discovery that MS was an immune mediated inflammatory disease paved the way for the treatments we know today. In 1993, interferon β‐1b became the first DMT for MS approved by the US Food and Drug Administration (FDA). Approvals for interferon β‐1a as well as glatiramer acetate (GA) soon followed. Today, we consider these the mildest immunosuppressant DMTs; however, their success verified that suppressing the immune system had a positive effect on the MS disease process.

Following these approvals, the disease process in MS is now better understood. Recently approved therapies include monoclonal antibodies, which affect other immune pathways. Today, there are 14 approved DMTs (Table 1). Although the advent of these newer DMTs has revolutionized care for patients with MS, it has been accompanied by increasing costs for the agents. Direct medical costs associated with MS management, coupled with indirect costs from lost productivity, have been estimated to be $24.2 billion annually in the US.¹ These increases have been seen across many levels of insurance coverage—private payer, Medicare, and the Veterans Health Administration (VHA).^2,3

The Figure demonstrates the cost increase that have been seen across VHA between 2004 and 2019 for the DMTs identified in Table 1. Indeed, this compound annual growth rate may be an underestimate because infusion therapies (eg, natalizumab, ocrelizumab, and alemtuzumab) are difficult to track as they may be dispensed directly via a Risk Evaluation Medication Strategy (REMS) program. According to the VHA Pharmacy Benefit Management Service (PBM), in September 2019, dimethyl fumarate (DMF) had the 13th highest total outpatient drug cost for the US Department of Veterans Affairs (VA), interferon β‐1a ranked 62nd and 83rd (prefilled pen and syringe, respectively), and GA 40 mg ranked 89th.

Factors Impacting DMT Use

Recent changes to MS typing have impacted utilization of DMTs. Traditionally, there were 4 subtypes of MS: relapsing remitting (RRMS), secondary progressive (SPMS), progressive relapsing (PRMS), and primary progressive (PPMS). These subtypes are now viewed more broadly and grouped as either relapsing or progressive. The traditional subtypes fall under these broader definitions. Additionally, SPMS has been broken into active SPMS, characterized by continued worsening of disability unrelated to acute relapses, superimposed with activity that can be seen on magnetic resonance images (MRIs), and nonactive SPMS, which has the same disability progression as active SPMS but without MRI-visible activity.^4-6 In 2019, these supplementary designations to SPMS made their first appearance in FDA-approved indications. All existing DMTs now include this terminology in their labelling and are indicated in active SPMS. There remain no DMTs that treat nonactive SPMS.

The current landscape of DMTs is highly varied in method of administration, risks, and benefits. As efficacy of these medications often is marked by how well they can prevent the immune system from attacking myelin, an inverse relationship between safety and efficacy results. The standard treatment outcomes in MS have evolved over time. The following are the commonly used primary outcomes in clinical trials: relapse reduction; increased time between relapses; decreased severity of relapses; prevention or extend time to disability milestones as measured by the Expanded Disability Status Scale (EDSS) and other disability measures; prevention or extension of time to onset of secondary progressive disease; prevention or reduction of the number and size of new and enhancing lesions on MRI; and limitation of overall MRI lesion burden in the central nervous system (CNS).

Newer treatment outcomes employed in more recent trials include: measures of axonal damage, CNS atrophy, evidence of microscopic disease via conventional MRI and advanced imaging modalities, biomarkers associated with inflammatory disease activity and neurodegeneration in MS, and the use of no evidence of disease activity (NEDA). These outcomes also must be evaluated by the safety concerns of each agent. Short- and long-term safety are critical factors in the selection of DMTs for MS. The injectable therapies for MS (interferon β‐1a, interferon β‐1b, and GA) have established long-term safety profiles from > 20 years of continuous use. The long-term safety profiles of oral immunomodulatory agents and monoclonal antibodies for these drugs in MS have yet to be determined. Safety concerns associated with some therapies and added requirements for safety monitoring may increase the complexity of a therapeutic selection.

Current cost minimization strategies for DMT include limiting DMT agents on formularies, tier systems that incentivize patients/prescribers to select the lowest priced agents on the formulary, negotiating arrangements with manufacturers to freeze prices or provide discounts in exchange for a priority position in the formulary, and requiring prior authorization to initiate or switch therapy. The use of generic medications and interchange to these agents from a brand name formulation can help reduce expense. Several of these strategies have been implemented in VHA.

Disease-Modifying Therapies

In 2019, 18,645 veterans with MS had either a MS-specific DMT or ≥ 1 annual encounters with a primary diagnosis of MS. Of this population, 4,720 were female and 13,357 were service connected according to VA data. About 50% of veterans with MS take a DMT. This percentage has remained stable over the past decade (Table 2). Although it appears the number of unique veterans prescribed an outpatient DMT is decreasing, this does not include the growing use of infused DMTs or DMTs obtained through the Veterans Choice Program (VCP)/Community Care (CC).

The overall outpatient pharmacy costs for veterans have remained constant despite the reduction in outpatient pharmacy prescription numbers. This may be due to increases in DMT cost to the VHA and the use of more expensive oral agents over the previously used platform injection DMTs.

Generic Conversion

GA is available in 20 mg daily and 40 mg3 times weekly subcutaneous injection dosing. The first evidence of clinical efficacy for a generic formulation for GA was evaluated by the GATE trial.⁷ This trial was a multicenter, randomized, double-blind, active- and placebo-controlled phase 3 trial. Eligible participants were randomized to receive daily SC injection for 9 months of 20 mg generic GA (n = 5,353), 20 mg brand GA (n = 5,357), or placebo (n = 584). The primary endpoint was the mean number of gadolinium (Gd1) lesions visible on MRIs during months 7, 8, and 9, which were significantly reduced in the combined GA-treated group and in each GA group individually when compared with the placebo group, confirming the study sensitivity (ie, GA was effective under the conditions of the study). Tolerability (including injection site reactions) and safety (incidence, spectrum, and severity of adverse events [AEs]) were similar in the generic and brand GA groups. These results demonstrated that generic and brand GA had equivalent efficacy, tolerability, and safety over a 9-month period.⁷

Results of a 15-month extension of the study were presented in 2015 and showed similar efficacy, safety, and tolerability in participants treated with generic GA for 2 years and patients switched from brand to generic GA.⁸ Multiple shifts for GA occurred, most notably the conversion from branded Copaxone (Teva Pharmaceutical Industries) to generic Glatopa (Sandoz). Subsequently, Sandoz released a generic 40 mg 3 times weekly formulation. Additionally, Mylan entered the generic GA market. With 3 competing manufacturers, internal data from the VHA indicated that it was able to negotiate a single source contract for this medication that provided a savings of $32,088,904.69 between September 2016 and May 2019.

The impact of generic conversions is just being realized. Soon, patents will begin to expire for oral DMTs, leading to an expected growth of generic alternatives. Already the FDA has approved 4 generic alternatives for teriflunomide, 3 for fingolimod (with 13 tentative approvals), and 15 generic alternatives for dimethyl fumarate (DMF). Implementation of therapeutic interchanges will be pursued by VHA as clinically supported by evidence.

Criteria for Use

PBM supports utilizing criteria to help guide providers on DMT options and promote safe, effective, and value-based selection of a DMT. The PBM creates monographs and criteria for use (CFU) for new medications. The monograph contains a literature evaluation of all studies available to date that concern both safety and efficacy of the new medication. Therapeutic alternatives also are presented and assessed for key elements that may determine the most safe and effective use. Additional safety areas for the new medications such as look-alike, sound-alike potential, special populations use (ie, those who are pregnant, the elderly, and those with liver or renal dysfunction), and drug-drug interactions are presented. Lastly, and possibly most importantly in an ever-growing growing world of DMTs, the monograph describes a reasonable place in therapy for the new DMT.

CFU are additional guidance for some DMTs. The development of CFU are based on several questions that arise during the monograph development for a DMT. These include, but are not limited to:

• Are there safety concerns that require the drug to receive a review to ensure safe prescribing (eg, agents with REMS programs, or safety concerns in specific populations)?
• Does the drug require a specialty provider type with knowledge and experience in those disease states to ensure appropriate and safe prescribing (eg restricted to infectious diseases)?
• Do VHA or non-VHA guidelines suggest alternative therapy be used prior to the agent?
• Is a review deemed necessary to ensure the preferred agent is used first (eg, second-line therapy)?

The CFU defines parameters of drug use consistent with high quality and evidence-based patient care. CFUs also serve as a basis for monitoring local, regional, and national patterns of pharmacologic care and help guide health care providers (HCPs) on appropriate use of medication.

CFUs are designed to ensure the HCP is safely starting a medication that has evidence for efficacy for their patient. For example, alemtuzumab is a high-risk, high-efficacy DMT. The alemtuzumab CFU acknowledges this by having exclusion criteria that prevent a veteran at high risk (ie, on another immunosuppressant) from being exposed to severe AEs (ie, severe leukopenia) that are associated with the medication. On the other hand, the inclusion criteria recognize the benefits of alemtuzumab and allows those with highly active MS who have failed other DMTs to receive the medication.

The drug monograph and CFU process is an important part of VHA efforts to optimize patient care. After a draft version is developed, HCPs can provide feedback on the exclusion/inclusion criteria and describe how they anticipate using the medication in their practice. This insight can be beneficial for MS treatment as diverse HCPs may have distinct viewpoints on how DMTs should be started. Pharmacists and physicians on a national level then discuss and decide together what to include in the final drafts of the drug monograph and CFU. Final documents are disseminated to all sites, which encourages consistent practices across the VHA.⁹ These documents are reviewed on a regular basis and updated as needed based on available literature evidence.

It is well accepted that early use of DMT correlates with lower accumulated long-term disability.¹⁰ However, discontinuation of DMT should be treated with equal importance. This benefits the patient by reducing their risk of AEs from DMTs and provides cost savings. Age and disease stability are factors to consider for DMT discontinuation. In a study with patients aged > 45 years and another with patients aged > 60 years, discontinuing DMT rarely had a negative impact and improved quality of life.^11,12 A retrospective meta-analysis of age-dependent efficacy of current DMTs predicted that DMT loses efficacy at age 53 years. In addition, higher efficacy DMT only outperforms lower efficacy DMT in patients aged < 40.5 years.¹³ Stability of disease and lack of relapses for ≥ 2 years also may be a positive predictor to safely discontinue DMT.^14,15 The growing literature to support safe discontinuation of DMT makes this a more convincing strategy to avoid unnecessary costs associated with current DMTs. With an average age of 59 years for veterans with MS, this may be one of the largest areas of cost avoidance to consider.

Off-Label Use

Other potential ways to reduce DMT costs is to consider off-label treatments. The OLYMPUS trial studied off-label use of rituximab, an anti-CD20 antibody like ocrelizumab. It did not meet statistical significance for its primary endpoint; however, in a subgroup analysis, off-label use was found to be more effective in a population aged < 51 years.¹⁶ Other case reports and smaller scale studies also describe rituximab’s efficacy in MS.^17,18 In 2018, the FDA approved the first rituximab biosimilar.¹⁹ Further competition from biosimilars likely will make rituximab an even more cost-effective choice when compared with ocrelizumab.

Alternate Dosing Regimens

Extended interval dosing of natalizumab has been studied, extending the standard infusion interval from every 4 weeks to 5- to 8-week intervals. One recent article compared these interval extensions and found that all extended intervals of up to 56 days did not increase new or enhancing lesions on MRI when compared with standard interval dosing.²⁰ Another larger randomized trial is underway to evaluate efficacy and safety of extended interval dosing of natalizumab (NCT03689972). Utilization of this dosing may reduce natalizumab annual costs by up to 50%.

Safety Monitoring

DMF is an oral DMT on the VHA formulary with CFU. Since leukopenia is a known AE, baseline and quarterly monitoring of the complete blood count (CBC) is recommended for patients taking DMF. Additionally, DMF should be held if white blood cell count (WBC) falls below 2,000/mm³.²¹ There have been recent reports of death secondary to progressive multifocal leukoencephalopathy (PML) among European patients taking DMF.^22-24 This has raised concerns about adherence to recommended CBC monitoring in veterans taking DMF. The association of DMF and leukopenia has been evident since early clinical trials.²⁵ Leukopenia in immunocompromised patients increases the risk of PML.

In the long-term extension study ENDORSE, 6% to 7% of patients continuing DMF had WBC counts of 3.0×10⁹/L compared with 7% to 10% in the new to DMF group.²⁶ In addition 6% to 8% of patients continuing DMF had lymphocyte counts of 0.5×10⁹/L, compared with 5% to 9% in the new to DMF group. The cases of PML occurred in patients who had low lymphocyte counts over an extended period with no adjustment to DMF therapy, such as holding the drug until WBC counts returned to normal levels or stopping the drug. Discussion and review within VHA resulted in the recommendation for quarterly WBC monitoring criteria.

PBM and VA Center for Medication Safety (MedSafe) conducted a medication usage evaluation (MUE) on adherence to the WBC monitoring set forth in the CFU. Data collection began in fourth quarter of fiscal year (FY) 2015 with the most recent reporting period of fourth quarter of FY 2017. The Medication Utilization Evaluation Tool tracks patients with no reported WBC in 90 days and WBC < 2,000/mm³. Over the reporting period, 20% to 23% of patients have not received appropriate quarterly monitoring. Additionally, there have been 4 cases where the WBC decreased below the threshold limit. To ensure safe and effective use of DMF, it is important to adhere to the monitoring requirements set forth in the CFU.

Impact of REMS and Special Distribution

As DMTs increase in efficacy, there are often more risks associated with them. Some of these high-risk medications, including natalizumab and alemtuzumab, have REMS programs and/or have special distribution procedures. Although REMS are imperative for patient safety, the complexity of these programs can be difficult to navigate, which can create a barrier to access. The PBM helps to assist all sites with navigating and adhering to required actions to dispense and administer these medications through a national Special Handling Drugs Microsoft SharePoint site, which provides access to REMS forms and procurement information when drugs are dispensed from specialty pharmacies. Easing this process nationwide empowers more sites to be confident they can dispense specialty medications appropriately.

Clinical Pharmacists

The VHA is unique in its utilization of pharmacists in outpatient clinic settings. Utilization of an interdisciplinary team for medication management has been highly used in VHA for areas like primary care; however, pharmacist involvement in specialty areas is on the rise and MS is no exception. Pharmacists stationed in clinics, such as neurology or spinal cord injury, can impact care for veterans with MS. Interdisciplinary teams that include a pharmacist have been shown to increase patient adherence to DMTs.²⁷ However, pharmacists often assist with medication education and monitoring, which adds an additional layer of safety to DMT treatment. At the VHA, pharmacists also can obtain a scope of practice that allows them to prescribe medications and increase access to care for veterans with MS.

Education

The VHA demonstrates how education on a disease state like MS can be distributed on a large, national scale through drug monographs, CFU, and Microsoft SharePoint sites. In addition, VHA has created the MS Centers of Excellence (MSCoE) that serve as a hub of specialized health care providers in all aspects of MS care.

A core function of the MSCoE is to provide education to both HCPs and patients. The MSCoE and its regional hubs support sites that may not have an HCP who specializes in MS by providing advice on DMT selection, how to obtain specialty medications, and monitoring that needs to be completed to ensure veterans’ safety. The MSCoE also has partnered with the National MS Society to hold a lecture series on topics in MS. This free series is available online to all HCPs who interact with patients who have MS and is a way that VA is extending its best practices and expertise beyond its own health care system. There also is a quarterly newsletter for veterans with MS that highlights new information on DMTs that can affect their care.

Conclusion

It is an exciting and challenging period in MS treatment. New DMTs are being approved and entering clinical trials at a rapid pace. These new DMT agents may offer increased efficacy, improvements in AE profiles, and the possibility of increased medication adherence—but often at a higher cost. The utilization of CFU and formulary management provides the ability to ensure the safe and appropriate use of medications by veterans, with a secondary outcome of controlling pharmacy expenditures.

The VHA had expenditures of $142,135,938 for DMT use in FY 2018. As the VHA sees the new contract prices for DMT in January 2020, we are reminded that costs will continue to rise with some pharmaceutical manufacturers implementing prices 8% to 11% higher than 2019 prices, when the consumer price index defines an increase of 1.0% for 2020 and 1.4% in 2021.²⁸ It is imperative that the VHA formulary be managed judiciously and the necessary measures be in place for VHA practitioners to enable effective, safe and value-based care to the veteran population.

Prior to the first approved disease modifying therapy (DMT) in the 1990s, treatment approaches for multiple sclerosis (MS) were not well understood. The discovery that MS was an immune mediated inflammatory disease paved the way for the treatments we know today. In 1993, interferon β‐1b became the first DMT for MS approved by the US Food and Drug Administration (FDA). Approvals for interferon β‐1a as well as glatiramer acetate (GA) soon followed. Today, we consider these the mildest immunosuppressant DMTs; however, their success verified that suppressing the immune system had a positive effect on the MS disease process.

Following these approvals, the disease process in MS is now better understood. Recently approved therapies include monoclonal antibodies, which affect other immune pathways. Today, there are 14 approved DMTs (Table 1). Although the advent of these newer DMTs has revolutionized care for patients with MS, it has been accompanied by increasing costs for the agents. Direct medical costs associated with MS management, coupled with indirect costs from lost productivity, have been estimated to be $24.2 billion annually in the US.¹ These increases have been seen across many levels of insurance coverage—private payer, Medicare, and the Veterans Health Administration (VHA).^2,3

The Figure demonstrates the cost increase that have been seen across VHA between 2004 and 2019 for the DMTs identified in Table 1. Indeed, this compound annual growth rate may be an underestimate because infusion therapies (eg, natalizumab, ocrelizumab, and alemtuzumab) are difficult to track as they may be dispensed directly via a Risk Evaluation Medication Strategy (REMS) program. According to the VHA Pharmacy Benefit Management Service (PBM), in September 2019, dimethyl fumarate (DMF) had the 13th highest total outpatient drug cost for the US Department of Veterans Affairs (VA), interferon β‐1a ranked 62nd and 83rd (prefilled pen and syringe, respectively), and GA 40 mg ranked 89th.

Factors Impacting DMT Use

Recent changes to MS typing have impacted utilization of DMTs. Traditionally, there were 4 subtypes of MS: relapsing remitting (RRMS), secondary progressive (SPMS), progressive relapsing (PRMS), and primary progressive (PPMS). These subtypes are now viewed more broadly and grouped as either relapsing or progressive. The traditional subtypes fall under these broader definitions. Additionally, SPMS has been broken into active SPMS, characterized by continued worsening of disability unrelated to acute relapses, superimposed with activity that can be seen on magnetic resonance images (MRIs), and nonactive SPMS, which has the same disability progression as active SPMS but without MRI-visible activity.^4-6 In 2019, these supplementary designations to SPMS made their first appearance in FDA-approved indications. All existing DMTs now include this terminology in their labelling and are indicated in active SPMS. There remain no DMTs that treat nonactive SPMS.

The current landscape of DMTs is highly varied in method of administration, risks, and benefits. As efficacy of these medications often is marked by how well they can prevent the immune system from attacking myelin, an inverse relationship between safety and efficacy results. The standard treatment outcomes in MS have evolved over time. The following are the commonly used primary outcomes in clinical trials: relapse reduction; increased time between relapses; decreased severity of relapses; prevention or extend time to disability milestones as measured by the Expanded Disability Status Scale (EDSS) and other disability measures; prevention or extension of time to onset of secondary progressive disease; prevention or reduction of the number and size of new and enhancing lesions on MRI; and limitation of overall MRI lesion burden in the central nervous system (CNS).

Newer treatment outcomes employed in more recent trials include: measures of axonal damage, CNS atrophy, evidence of microscopic disease via conventional MRI and advanced imaging modalities, biomarkers associated with inflammatory disease activity and neurodegeneration in MS, and the use of no evidence of disease activity (NEDA). These outcomes also must be evaluated by the safety concerns of each agent. Short- and long-term safety are critical factors in the selection of DMTs for MS. The injectable therapies for MS (interferon β‐1a, interferon β‐1b, and GA) have established long-term safety profiles from > 20 years of continuous use. The long-term safety profiles of oral immunomodulatory agents and monoclonal antibodies for these drugs in MS have yet to be determined. Safety concerns associated with some therapies and added requirements for safety monitoring may increase the complexity of a therapeutic selection.

Current cost minimization strategies for DMT include limiting DMT agents on formularies, tier systems that incentivize patients/prescribers to select the lowest priced agents on the formulary, negotiating arrangements with manufacturers to freeze prices or provide discounts in exchange for a priority position in the formulary, and requiring prior authorization to initiate or switch therapy. The use of generic medications and interchange to these agents from a brand name formulation can help reduce expense. Several of these strategies have been implemented in VHA.

Disease-Modifying Therapies

In 2019, 18,645 veterans with MS had either a MS-specific DMT or ≥ 1 annual encounters with a primary diagnosis of MS. Of this population, 4,720 were female and 13,357 were service connected according to VA data. About 50% of veterans with MS take a DMT. This percentage has remained stable over the past decade (Table 2). Although it appears the number of unique veterans prescribed an outpatient DMT is decreasing, this does not include the growing use of infused DMTs or DMTs obtained through the Veterans Choice Program (VCP)/Community Care (CC).

The overall outpatient pharmacy costs for veterans have remained constant despite the reduction in outpatient pharmacy prescription numbers. This may be due to increases in DMT cost to the VHA and the use of more expensive oral agents over the previously used platform injection DMTs.

Generic Conversion

GA is available in 20 mg daily and 40 mg3 times weekly subcutaneous injection dosing. The first evidence of clinical efficacy for a generic formulation for GA was evaluated by the GATE trial.⁷ This trial was a multicenter, randomized, double-blind, active- and placebo-controlled phase 3 trial. Eligible participants were randomized to receive daily SC injection for 9 months of 20 mg generic GA (n = 5,353), 20 mg brand GA (n = 5,357), or placebo (n = 584). The primary endpoint was the mean number of gadolinium (Gd1) lesions visible on MRIs during months 7, 8, and 9, which were significantly reduced in the combined GA-treated group and in each GA group individually when compared with the placebo group, confirming the study sensitivity (ie, GA was effective under the conditions of the study). Tolerability (including injection site reactions) and safety (incidence, spectrum, and severity of adverse events [AEs]) were similar in the generic and brand GA groups. These results demonstrated that generic and brand GA had equivalent efficacy, tolerability, and safety over a 9-month period.⁷

Results of a 15-month extension of the study were presented in 2015 and showed similar efficacy, safety, and tolerability in participants treated with generic GA for 2 years and patients switched from brand to generic GA.⁸ Multiple shifts for GA occurred, most notably the conversion from branded Copaxone (Teva Pharmaceutical Industries) to generic Glatopa (Sandoz). Subsequently, Sandoz released a generic 40 mg 3 times weekly formulation. Additionally, Mylan entered the generic GA market. With 3 competing manufacturers, internal data from the VHA indicated that it was able to negotiate a single source contract for this medication that provided a savings of $32,088,904.69 between September 2016 and May 2019.

The impact of generic conversions is just being realized. Soon, patents will begin to expire for oral DMTs, leading to an expected growth of generic alternatives. Already the FDA has approved 4 generic alternatives for teriflunomide, 3 for fingolimod (with 13 tentative approvals), and 15 generic alternatives for dimethyl fumarate (DMF). Implementation of therapeutic interchanges will be pursued by VHA as clinically supported by evidence.

Criteria for Use

PBM supports utilizing criteria to help guide providers on DMT options and promote safe, effective, and value-based selection of a DMT. The PBM creates monographs and criteria for use (CFU) for new medications. The monograph contains a literature evaluation of all studies available to date that concern both safety and efficacy of the new medication. Therapeutic alternatives also are presented and assessed for key elements that may determine the most safe and effective use. Additional safety areas for the new medications such as look-alike, sound-alike potential, special populations use (ie, those who are pregnant, the elderly, and those with liver or renal dysfunction), and drug-drug interactions are presented. Lastly, and possibly most importantly in an ever-growing growing world of DMTs, the monograph describes a reasonable place in therapy for the new DMT.

CFU are additional guidance for some DMTs. The development of CFU are based on several questions that arise during the monograph development for a DMT. These include, but are not limited to:

• Are there safety concerns that require the drug to receive a review to ensure safe prescribing (eg, agents with REMS programs, or safety concerns in specific populations)?
• Does the drug require a specialty provider type with knowledge and experience in those disease states to ensure appropriate and safe prescribing (eg restricted to infectious diseases)?
• Do VHA or non-VHA guidelines suggest alternative therapy be used prior to the agent?
• Is a review deemed necessary to ensure the preferred agent is used first (eg, second-line therapy)?

The CFU defines parameters of drug use consistent with high quality and evidence-based patient care. CFUs also serve as a basis for monitoring local, regional, and national patterns of pharmacologic care and help guide health care providers (HCPs) on appropriate use of medication.

CFUs are designed to ensure the HCP is safely starting a medication that has evidence for efficacy for their patient. For example, alemtuzumab is a high-risk, high-efficacy DMT. The alemtuzumab CFU acknowledges this by having exclusion criteria that prevent a veteran at high risk (ie, on another immunosuppressant) from being exposed to severe AEs (ie, severe leukopenia) that are associated with the medication. On the other hand, the inclusion criteria recognize the benefits of alemtuzumab and allows those with highly active MS who have failed other DMTs to receive the medication.

The drug monograph and CFU process is an important part of VHA efforts to optimize patient care. After a draft version is developed, HCPs can provide feedback on the exclusion/inclusion criteria and describe how they anticipate using the medication in their practice. This insight can be beneficial for MS treatment as diverse HCPs may have distinct viewpoints on how DMTs should be started. Pharmacists and physicians on a national level then discuss and decide together what to include in the final drafts of the drug monograph and CFU. Final documents are disseminated to all sites, which encourages consistent practices across the VHA.⁹ These documents are reviewed on a regular basis and updated as needed based on available literature evidence.

It is well accepted that early use of DMT correlates with lower accumulated long-term disability.¹⁰ However, discontinuation of DMT should be treated with equal importance. This benefits the patient by reducing their risk of AEs from DMTs and provides cost savings. Age and disease stability are factors to consider for DMT discontinuation. In a study with patients aged > 45 years and another with patients aged > 60 years, discontinuing DMT rarely had a negative impact and improved quality of life.^11,12 A retrospective meta-analysis of age-dependent efficacy of current DMTs predicted that DMT loses efficacy at age 53 years. In addition, higher efficacy DMT only outperforms lower efficacy DMT in patients aged < 40.5 years.¹³ Stability of disease and lack of relapses for ≥ 2 years also may be a positive predictor to safely discontinue DMT.^14,15 The growing literature to support safe discontinuation of DMT makes this a more convincing strategy to avoid unnecessary costs associated with current DMTs. With an average age of 59 years for veterans with MS, this may be one of the largest areas of cost avoidance to consider.

Off-Label Use

Other potential ways to reduce DMT costs is to consider off-label treatments. The OLYMPUS trial studied off-label use of rituximab, an anti-CD20 antibody like ocrelizumab. It did not meet statistical significance for its primary endpoint; however, in a subgroup analysis, off-label use was found to be more effective in a population aged < 51 years.¹⁶ Other case reports and smaller scale studies also describe rituximab’s efficacy in MS.^17,18 In 2018, the FDA approved the first rituximab biosimilar.¹⁹ Further competition from biosimilars likely will make rituximab an even more cost-effective choice when compared with ocrelizumab.

Alternate Dosing Regimens

Extended interval dosing of natalizumab has been studied, extending the standard infusion interval from every 4 weeks to 5- to 8-week intervals. One recent article compared these interval extensions and found that all extended intervals of up to 56 days did not increase new or enhancing lesions on MRI when compared with standard interval dosing.²⁰ Another larger randomized trial is underway to evaluate efficacy and safety of extended interval dosing of natalizumab (NCT03689972). Utilization of this dosing may reduce natalizumab annual costs by up to 50%.

Safety Monitoring

DMF is an oral DMT on the VHA formulary with CFU. Since leukopenia is a known AE, baseline and quarterly monitoring of the complete blood count (CBC) is recommended for patients taking DMF. Additionally, DMF should be held if white blood cell count (WBC) falls below 2,000/mm³.²¹ There have been recent reports of death secondary to progressive multifocal leukoencephalopathy (PML) among European patients taking DMF.^22-24 This has raised concerns about adherence to recommended CBC monitoring in veterans taking DMF. The association of DMF and leukopenia has been evident since early clinical trials.²⁵ Leukopenia in immunocompromised patients increases the risk of PML.

In the long-term extension study ENDORSE, 6% to 7% of patients continuing DMF had WBC counts of 3.0×10⁹/L compared with 7% to 10% in the new to DMF group.²⁶ In addition 6% to 8% of patients continuing DMF had lymphocyte counts of 0.5×10⁹/L, compared with 5% to 9% in the new to DMF group. The cases of PML occurred in patients who had low lymphocyte counts over an extended period with no adjustment to DMF therapy, such as holding the drug until WBC counts returned to normal levels or stopping the drug. Discussion and review within VHA resulted in the recommendation for quarterly WBC monitoring criteria.

PBM and VA Center for Medication Safety (MedSafe) conducted a medication usage evaluation (MUE) on adherence to the WBC monitoring set forth in the CFU. Data collection began in fourth quarter of fiscal year (FY) 2015 with the most recent reporting period of fourth quarter of FY 2017. The Medication Utilization Evaluation Tool tracks patients with no reported WBC in 90 days and WBC < 2,000/mm³. Over the reporting period, 20% to 23% of patients have not received appropriate quarterly monitoring. Additionally, there have been 4 cases where the WBC decreased below the threshold limit. To ensure safe and effective use of DMF, it is important to adhere to the monitoring requirements set forth in the CFU.

Impact of REMS and Special Distribution

As DMTs increase in efficacy, there are often more risks associated with them. Some of these high-risk medications, including natalizumab and alemtuzumab, have REMS programs and/or have special distribution procedures. Although REMS are imperative for patient safety, the complexity of these programs can be difficult to navigate, which can create a barrier to access. The PBM helps to assist all sites with navigating and adhering to required actions to dispense and administer these medications through a national Special Handling Drugs Microsoft SharePoint site, which provides access to REMS forms and procurement information when drugs are dispensed from specialty pharmacies. Easing this process nationwide empowers more sites to be confident they can dispense specialty medications appropriately.

Clinical Pharmacists

The VHA is unique in its utilization of pharmacists in outpatient clinic settings. Utilization of an interdisciplinary team for medication management has been highly used in VHA for areas like primary care; however, pharmacist involvement in specialty areas is on the rise and MS is no exception. Pharmacists stationed in clinics, such as neurology or spinal cord injury, can impact care for veterans with MS. Interdisciplinary teams that include a pharmacist have been shown to increase patient adherence to DMTs.²⁷ However, pharmacists often assist with medication education and monitoring, which adds an additional layer of safety to DMT treatment. At the VHA, pharmacists also can obtain a scope of practice that allows them to prescribe medications and increase access to care for veterans with MS.

Education

The VHA demonstrates how education on a disease state like MS can be distributed on a large, national scale through drug monographs, CFU, and Microsoft SharePoint sites. In addition, VHA has created the MS Centers of Excellence (MSCoE) that serve as a hub of specialized health care providers in all aspects of MS care.

A core function of the MSCoE is to provide education to both HCPs and patients. The MSCoE and its regional hubs support sites that may not have an HCP who specializes in MS by providing advice on DMT selection, how to obtain specialty medications, and monitoring that needs to be completed to ensure veterans’ safety. The MSCoE also has partnered with the National MS Society to hold a lecture series on topics in MS. This free series is available online to all HCPs who interact with patients who have MS and is a way that VA is extending its best practices and expertise beyond its own health care system. There also is a quarterly newsletter for veterans with MS that highlights new information on DMTs that can affect their care.

Conclusion

It is an exciting and challenging period in MS treatment. New DMTs are being approved and entering clinical trials at a rapid pace. These new DMT agents may offer increased efficacy, improvements in AE profiles, and the possibility of increased medication adherence—but often at a higher cost. The utilization of CFU and formulary management provides the ability to ensure the safe and appropriate use of medications by veterans, with a secondary outcome of controlling pharmacy expenditures.

The VHA had expenditures of $142,135,938 for DMT use in FY 2018. As the VHA sees the new contract prices for DMT in January 2020, we are reminded that costs will continue to rise with some pharmaceutical manufacturers implementing prices 8% to 11% higher than 2019 prices, when the consumer price index defines an increase of 1.0% for 2020 and 1.4% in 2021.²⁸ It is imperative that the VHA formulary be managed judiciously and the necessary measures be in place for VHA practitioners to enable effective, safe and value-based care to the veteran population.

Prior to the first approved disease modifying therapy (DMT) in the 1990s, treatment approaches for multiple sclerosis (MS) were not well understood. The discovery that MS was an immune mediated inflammatory disease paved the way for the treatments we know today. In 1993, interferon β‐1b became the first DMT for MS approved by the US Food and Drug Administration (FDA). Approvals for interferon β‐1a as well as glatiramer acetate (GA) soon followed. Today, we consider these the mildest immunosuppressant DMTs; however, their success verified that suppressing the immune system had a positive effect on the MS disease process.

Following these approvals, the disease process in MS is now better understood. Recently approved therapies include monoclonal antibodies, which affect other immune pathways. Today, there are 14 approved DMTs (Table 1). Although the advent of these newer DMTs has revolutionized care for patients with MS, it has been accompanied by increasing costs for the agents. Direct medical costs associated with MS management, coupled with indirect costs from lost productivity, have been estimated to be $24.2 billion annually in the US.¹ These increases have been seen across many levels of insurance coverage—private payer, Medicare, and the Veterans Health Administration (VHA).^2,3

The Figure demonstrates the cost increase that have been seen across VHA between 2004 and 2019 for the DMTs identified in Table 1. Indeed, this compound annual growth rate may be an underestimate because infusion therapies (eg, natalizumab, ocrelizumab, and alemtuzumab) are difficult to track as they may be dispensed directly via a Risk Evaluation Medication Strategy (REMS) program. According to the VHA Pharmacy Benefit Management Service (PBM), in September 2019, dimethyl fumarate (DMF) had the 13th highest total outpatient drug cost for the US Department of Veterans Affairs (VA), interferon β‐1a ranked 62nd and 83rd (prefilled pen and syringe, respectively), and GA 40 mg ranked 89th.

Factors Impacting DMT Use

Recent changes to MS typing have impacted utilization of DMTs. Traditionally, there were 4 subtypes of MS: relapsing remitting (RRMS), secondary progressive (SPMS), progressive relapsing (PRMS), and primary progressive (PPMS). These subtypes are now viewed more broadly and grouped as either relapsing or progressive. The traditional subtypes fall under these broader definitions. Additionally, SPMS has been broken into active SPMS, characterized by continued worsening of disability unrelated to acute relapses, superimposed with activity that can be seen on magnetic resonance images (MRIs), and nonactive SPMS, which has the same disability progression as active SPMS but without MRI-visible activity.^4-6 In 2019, these supplementary designations to SPMS made their first appearance in FDA-approved indications. All existing DMTs now include this terminology in their labelling and are indicated in active SPMS. There remain no DMTs that treat nonactive SPMS.

The current landscape of DMTs is highly varied in method of administration, risks, and benefits. As efficacy of these medications often is marked by how well they can prevent the immune system from attacking myelin, an inverse relationship between safety and efficacy results. The standard treatment outcomes in MS have evolved over time. The following are the commonly used primary outcomes in clinical trials: relapse reduction; increased time between relapses; decreased severity of relapses; prevention or extend time to disability milestones as measured by the Expanded Disability Status Scale (EDSS) and other disability measures; prevention or extension of time to onset of secondary progressive disease; prevention or reduction of the number and size of new and enhancing lesions on MRI; and limitation of overall MRI lesion burden in the central nervous system (CNS).

Newer treatment outcomes employed in more recent trials include: measures of axonal damage, CNS atrophy, evidence of microscopic disease via conventional MRI and advanced imaging modalities, biomarkers associated with inflammatory disease activity and neurodegeneration in MS, and the use of no evidence of disease activity (NEDA). These outcomes also must be evaluated by the safety concerns of each agent. Short- and long-term safety are critical factors in the selection of DMTs for MS. The injectable therapies for MS (interferon β‐1a, interferon β‐1b, and GA) have established long-term safety profiles from > 20 years of continuous use. The long-term safety profiles of oral immunomodulatory agents and monoclonal antibodies for these drugs in MS have yet to be determined. Safety concerns associated with some therapies and added requirements for safety monitoring may increase the complexity of a therapeutic selection.

Current cost minimization strategies for DMT include limiting DMT agents on formularies, tier systems that incentivize patients/prescribers to select the lowest priced agents on the formulary, negotiating arrangements with manufacturers to freeze prices or provide discounts in exchange for a priority position in the formulary, and requiring prior authorization to initiate or switch therapy. The use of generic medications and interchange to these agents from a brand name formulation can help reduce expense. Several of these strategies have been implemented in VHA.

Disease-Modifying Therapies

In 2019, 18,645 veterans with MS had either a MS-specific DMT or ≥ 1 annual encounters with a primary diagnosis of MS. Of this population, 4,720 were female and 13,357 were service connected according to VA data. About 50% of veterans with MS take a DMT. This percentage has remained stable over the past decade (Table 2). Although it appears the number of unique veterans prescribed an outpatient DMT is decreasing, this does not include the growing use of infused DMTs or DMTs obtained through the Veterans Choice Program (VCP)/Community Care (CC).

The overall outpatient pharmacy costs for veterans have remained constant despite the reduction in outpatient pharmacy prescription numbers. This may be due to increases in DMT cost to the VHA and the use of more expensive oral agents over the previously used platform injection DMTs.

Generic Conversion

GA is available in 20 mg daily and 40 mg3 times weekly subcutaneous injection dosing. The first evidence of clinical efficacy for a generic formulation for GA was evaluated by the GATE trial.⁷ This trial was a multicenter, randomized, double-blind, active- and placebo-controlled phase 3 trial. Eligible participants were randomized to receive daily SC injection for 9 months of 20 mg generic GA (n = 5,353), 20 mg brand GA (n = 5,357), or placebo (n = 584). The primary endpoint was the mean number of gadolinium (Gd1) lesions visible on MRIs during months 7, 8, and 9, which were significantly reduced in the combined GA-treated group and in each GA group individually when compared with the placebo group, confirming the study sensitivity (ie, GA was effective under the conditions of the study). Tolerability (including injection site reactions) and safety (incidence, spectrum, and severity of adverse events [AEs]) were similar in the generic and brand GA groups. These results demonstrated that generic and brand GA had equivalent efficacy, tolerability, and safety over a 9-month period.⁷

Results of a 15-month extension of the study were presented in 2015 and showed similar efficacy, safety, and tolerability in participants treated with generic GA for 2 years and patients switched from brand to generic GA.⁸ Multiple shifts for GA occurred, most notably the conversion from branded Copaxone (Teva Pharmaceutical Industries) to generic Glatopa (Sandoz). Subsequently, Sandoz released a generic 40 mg 3 times weekly formulation. Additionally, Mylan entered the generic GA market. With 3 competing manufacturers, internal data from the VHA indicated that it was able to negotiate a single source contract for this medication that provided a savings of $32,088,904.69 between September 2016 and May 2019.

The impact of generic conversions is just being realized. Soon, patents will begin to expire for oral DMTs, leading to an expected growth of generic alternatives. Already the FDA has approved 4 generic alternatives for teriflunomide, 3 for fingolimod (with 13 tentative approvals), and 15 generic alternatives for dimethyl fumarate (DMF). Implementation of therapeutic interchanges will be pursued by VHA as clinically supported by evidence.

Criteria for Use

PBM supports utilizing criteria to help guide providers on DMT options and promote safe, effective, and value-based selection of a DMT. The PBM creates monographs and criteria for use (CFU) for new medications. The monograph contains a literature evaluation of all studies available to date that concern both safety and efficacy of the new medication. Therapeutic alternatives also are presented and assessed for key elements that may determine the most safe and effective use. Additional safety areas for the new medications such as look-alike, sound-alike potential, special populations use (ie, those who are pregnant, the elderly, and those with liver or renal dysfunction), and drug-drug interactions are presented. Lastly, and possibly most importantly in an ever-growing growing world of DMTs, the monograph describes a reasonable place in therapy for the new DMT.

CFU are additional guidance for some DMTs. The development of CFU are based on several questions that arise during the monograph development for a DMT. These include, but are not limited to:

• Are there safety concerns that require the drug to receive a review to ensure safe prescribing (eg, agents with REMS programs, or safety concerns in specific populations)?
• Does the drug require a specialty provider type with knowledge and experience in those disease states to ensure appropriate and safe prescribing (eg restricted to infectious diseases)?
• Do VHA or non-VHA guidelines suggest alternative therapy be used prior to the agent?
• Is a review deemed necessary to ensure the preferred agent is used first (eg, second-line therapy)?

The CFU defines parameters of drug use consistent with high quality and evidence-based patient care. CFUs also serve as a basis for monitoring local, regional, and national patterns of pharmacologic care and help guide health care providers (HCPs) on appropriate use of medication.

CFUs are designed to ensure the HCP is safely starting a medication that has evidence for efficacy for their patient. For example, alemtuzumab is a high-risk, high-efficacy DMT. The alemtuzumab CFU acknowledges this by having exclusion criteria that prevent a veteran at high risk (ie, on another immunosuppressant) from being exposed to severe AEs (ie, severe leukopenia) that are associated with the medication. On the other hand, the inclusion criteria recognize the benefits of alemtuzumab and allows those with highly active MS who have failed other DMTs to receive the medication.

The drug monograph and CFU process is an important part of VHA efforts to optimize patient care. After a draft version is developed, HCPs can provide feedback on the exclusion/inclusion criteria and describe how they anticipate using the medication in their practice. This insight can be beneficial for MS treatment as diverse HCPs may have distinct viewpoints on how DMTs should be started. Pharmacists and physicians on a national level then discuss and decide together what to include in the final drafts of the drug monograph and CFU. Final documents are disseminated to all sites, which encourages consistent practices across the VHA.⁹ These documents are reviewed on a regular basis and updated as needed based on available literature evidence.

It is well accepted that early use of DMT correlates with lower accumulated long-term disability.¹⁰ However, discontinuation of DMT should be treated with equal importance. This benefits the patient by reducing their risk of AEs from DMTs and provides cost savings. Age and disease stability are factors to consider for DMT discontinuation. In a study with patients aged > 45 years and another with patients aged > 60 years, discontinuing DMT rarely had a negative impact and improved quality of life.^11,12 A retrospective meta-analysis of age-dependent efficacy of current DMTs predicted that DMT loses efficacy at age 53 years. In addition, higher efficacy DMT only outperforms lower efficacy DMT in patients aged < 40.5 years.¹³ Stability of disease and lack of relapses for ≥ 2 years also may be a positive predictor to safely discontinue DMT.^14,15 The growing literature to support safe discontinuation of DMT makes this a more convincing strategy to avoid unnecessary costs associated with current DMTs. With an average age of 59 years for veterans with MS, this may be one of the largest areas of cost avoidance to consider.

Off-Label Use

Other potential ways to reduce DMT costs is to consider off-label treatments. The OLYMPUS trial studied off-label use of rituximab, an anti-CD20 antibody like ocrelizumab. It did not meet statistical significance for its primary endpoint; however, in a subgroup analysis, off-label use was found to be more effective in a population aged < 51 years.¹⁶ Other case reports and smaller scale studies also describe rituximab’s efficacy in MS.^17,18 In 2018, the FDA approved the first rituximab biosimilar.¹⁹ Further competition from biosimilars likely will make rituximab an even more cost-effective choice when compared with ocrelizumab.

Alternate Dosing Regimens

Extended interval dosing of natalizumab has been studied, extending the standard infusion interval from every 4 weeks to 5- to 8-week intervals. One recent article compared these interval extensions and found that all extended intervals of up to 56 days did not increase new or enhancing lesions on MRI when compared with standard interval dosing.²⁰ Another larger randomized trial is underway to evaluate efficacy and safety of extended interval dosing of natalizumab (NCT03689972). Utilization of this dosing may reduce natalizumab annual costs by up to 50%.

Safety Monitoring

DMF is an oral DMT on the VHA formulary with CFU. Since leukopenia is a known AE, baseline and quarterly monitoring of the complete blood count (CBC) is recommended for patients taking DMF. Additionally, DMF should be held if white blood cell count (WBC) falls below 2,000/mm³.²¹ There have been recent reports of death secondary to progressive multifocal leukoencephalopathy (PML) among European patients taking DMF.^22-24 This has raised concerns about adherence to recommended CBC monitoring in veterans taking DMF. The association of DMF and leukopenia has been evident since early clinical trials.²⁵ Leukopenia in immunocompromised patients increases the risk of PML.

In the long-term extension study ENDORSE, 6% to 7% of patients continuing DMF had WBC counts of 3.0×10⁹/L compared with 7% to 10% in the new to DMF group.²⁶ In addition 6% to 8% of patients continuing DMF had lymphocyte counts of 0.5×10⁹/L, compared with 5% to 9% in the new to DMF group. The cases of PML occurred in patients who had low lymphocyte counts over an extended period with no adjustment to DMF therapy, such as holding the drug until WBC counts returned to normal levels or stopping the drug. Discussion and review within VHA resulted in the recommendation for quarterly WBC monitoring criteria.

PBM and VA Center for Medication Safety (MedSafe) conducted a medication usage evaluation (MUE) on adherence to the WBC monitoring set forth in the CFU. Data collection began in fourth quarter of fiscal year (FY) 2015 with the most recent reporting period of fourth quarter of FY 2017. The Medication Utilization Evaluation Tool tracks patients with no reported WBC in 90 days and WBC < 2,000/mm³. Over the reporting period, 20% to 23% of patients have not received appropriate quarterly monitoring. Additionally, there have been 4 cases where the WBC decreased below the threshold limit. To ensure safe and effective use of DMF, it is important to adhere to the monitoring requirements set forth in the CFU.

Impact of REMS and Special Distribution

As DMTs increase in efficacy, there are often more risks associated with them. Some of these high-risk medications, including natalizumab and alemtuzumab, have REMS programs and/or have special distribution procedures. Although REMS are imperative for patient safety, the complexity of these programs can be difficult to navigate, which can create a barrier to access. The PBM helps to assist all sites with navigating and adhering to required actions to dispense and administer these medications through a national Special Handling Drugs Microsoft SharePoint site, which provides access to REMS forms and procurement information when drugs are dispensed from specialty pharmacies. Easing this process nationwide empowers more sites to be confident they can dispense specialty medications appropriately.

Clinical Pharmacists

The VHA is unique in its utilization of pharmacists in outpatient clinic settings. Utilization of an interdisciplinary team for medication management has been highly used in VHA for areas like primary care; however, pharmacist involvement in specialty areas is on the rise and MS is no exception. Pharmacists stationed in clinics, such as neurology or spinal cord injury, can impact care for veterans with MS. Interdisciplinary teams that include a pharmacist have been shown to increase patient adherence to DMTs.²⁷ However, pharmacists often assist with medication education and monitoring, which adds an additional layer of safety to DMT treatment. At the VHA, pharmacists also can obtain a scope of practice that allows them to prescribe medications and increase access to care for veterans with MS.

Education

The VHA demonstrates how education on a disease state like MS can be distributed on a large, national scale through drug monographs, CFU, and Microsoft SharePoint sites. In addition, VHA has created the MS Centers of Excellence (MSCoE) that serve as a hub of specialized health care providers in all aspects of MS care.

A core function of the MSCoE is to provide education to both HCPs and patients. The MSCoE and its regional hubs support sites that may not have an HCP who specializes in MS by providing advice on DMT selection, how to obtain specialty medications, and monitoring that needs to be completed to ensure veterans’ safety. The MSCoE also has partnered with the National MS Society to hold a lecture series on topics in MS. This free series is available online to all HCPs who interact with patients who have MS and is a way that VA is extending its best practices and expertise beyond its own health care system. There also is a quarterly newsletter for veterans with MS that highlights new information on DMTs that can affect their care.

Conclusion

It is an exciting and challenging period in MS treatment. New DMTs are being approved and entering clinical trials at a rapid pace. These new DMT agents may offer increased efficacy, improvements in AE profiles, and the possibility of increased medication adherence—but often at a higher cost. The utilization of CFU and formulary management provides the ability to ensure the safe and appropriate use of medications by veterans, with a secondary outcome of controlling pharmacy expenditures.

The VHA had expenditures of $142,135,938 for DMT use in FY 2018. As the VHA sees the new contract prices for DMT in January 2020, we are reminded that costs will continue to rise with some pharmaceutical manufacturers implementing prices 8% to 11% higher than 2019 prices, when the consumer price index defines an increase of 1.0% for 2020 and 1.4% in 2021.²⁸ It is imperative that the VHA formulary be managed judiciously and the necessary measures be in place for VHA practitioners to enable effective, safe and value-based care to the veteran population.