Three patients were waiting in a queue for their telemedicine visit. Four others were in exam rooms, waiting for their appointments. Another patient was on the phone, requesting a prescription renewal.

On a sunny Wednesday afternoon in February, David Ahdoot, MD, FACOG, an ob.gyn. in Burbank, Calif., about 10 miles north of downtown Los Angeles, knows he’ll be working late.

“Normally, we would be closed on Wednesday afternoon,” he said. That time would ordinarily be used to schedule surgeries, make dictation, and perform other tasks. But those were the old days, before the COVID-19 pandemic, before the ob.gyn. shortage got even worse, and before many of the other obstacles that make his practice more burdensome worsened.

Those Wednesday afternoon tasks must be done another time. “There are too many patients to see in the office,” said Dr. Ahdoot, who’s also an assistant clinical professor at UCLA. Because of the shortage of primary care physicians, he has taken on new patients, although he said he would like to focus on his existing ones.

Many of those existing patients have been coming to Dr. Ahdoot for years. “I love my job,” he said, and it shows.

His patient reviews online include the usual grumblings about waiting time and being rushed, but many, especially those from new parents, praise him as caring, compassionate, exceptional – the kind of doctor women trust to deliver their first baby and their next ones, then guide them through menopause and other issues.

The shortage of ob.gyns. in California, as elsewhere, is real, as Dr. Ahdoot’s day-to-day attests. The implications are in evidence well beyond his higher patient loads. Lately, Dr. Ahdoot said, the calls from headhunters seeking to fill positions for locum tenens have increased from twice a month to three times a day. Despite his love for his practice, he admits he thinks about stepping away. He is 56, 8 years short of the average retirement age for ob.gyns. nationally, according to a 2018 report.
 

Projected shortages

The shortage of primary care doctors, including ob.gyns., is nationwide. Dr. Ahdoot is one of many faces behind the statistics. According to a 2021 update from the U.S. Department of Health & Human Services, the number of ob.gyns. nationwide is expected to decrease 7% between 2018 and 2030, from 50,850 to 47,490. Meanwhile, demand is headed in the other direction – it is projected to rise 4%, from 50,850 to 52,660 ob.gyns. needed. The need for nurse-midwives, nurse-practitioners, and physician assistants who provide women’s health care is also expected to exceed the supply in coming years.

Some areas are harder hit. The Northeast is expected to have enough maternal health care providers to meet the current average level of care nationally but the West, Midwest, and South will not, according to HHS.

California will likely need an additional 4,700 primary care clinicians by 2025, according to projections by the HealthForce Center at the University of California, San Francisco.
 

Solutions in sight?

Efforts are increasing to make it easier or more appealing for ob.gyns. to practice, or remain in practice, in California. Some existing programs have received funding, while new initiatives to improve the situation are launching.

Some of these efforts and programs will be viewed as a model by some other states, said Janet Coffman, PhD, associate professor at UC San Francisco and a health policy expert who is familiar with new programs and established ones.

“I would say that California offers an example of a multifaceted approach to addressing the shortage of reproductive health providers in general and abortion providers in particular.”

The state has not sat idly in the face of dire predictions of shortfalls in the number of ob.gyns. Over the past decade, Dr. Coffman said, the legislature has “substantially” boosted funding for grants to support ob.gyn. residency programs through CalMedForce and the Song-Brown Healthcare Workforce Training Program. The result: an 18% increase in the number of residents entering the field over the past decade.

“These programs have also substantially increased funding for family medicine residency programs, which are important because family physicians are trained to provide preventive reproductive health services and manage low-risk deliveries,” she added. “Funding for midwifery, nurse midwifery, and nurse practitioner education has been more modest, which I find disappointing because they are qualified to provide many reproductive health services and are more likely to care for underserved populations.”

Other new programs and legislation are focused on expanding the scope of practice for nonphysician health care providers who care for women. Many of these measures are meant to ensure continued access to abortion services not just for California residents, who are guaranteed that right in the state constitution, but for the influx of women expected from states that limited or prohibited abortion after the overturn of Roe v. Wade.

Gavin Newsom, the state’s Democratic governor, has promoted California as a safe haven for women seeking abortions. In September, Gov. Newsom’s reelection campaign rented billboards in six states that have restrictive abortion laws with messages directing women to a website informing them “abortion is legal and protected in California.” The website includes a search function for women looking for providers – representing a further potential strain on the already stressed pool of clinicians. Each year, an estimated 8,000 to 16,100 more people are expected to travel to California for abortions, according to projections made in 2022 by the UCLA Center on Reproductive Health, Law, and Policy.

The questions are, will the efforts be enough to stall or reverse the shortage, and will the efforts to expand other health care providers’ scope of practice be met with cooperation or resistance by MDs?
 

Just launched: California reproductive health service corps

Brand new, as of January 2023, is the California Reproductive Health Service Corps, created by a bill Gov. Newsom signed into law last September. The program operates within the Department of Health Care Access and Information. Rajeena Victoria Bisla, a spokesperson for assemblywoman Cottie Petrie-Norris (D-Irvine), who authored the bill, said: “The Corps will be responsible for recruiting, training, and retaining a diverse workforce of health care professionals who will be part of reproductive health care teams assigned to work in underserved areas.”

The teams will include MDs as well as licensed midwives, nurses, physician’s assistants, doulas, and medical assistants. They will provide abortion care, contraception, perinatal care, gynecology services, and gender-affirming care, among other needs, Ms. Bisla said.

The California Medical Association’s philanthropic arm, Physicians for a Healthy California (PHC), has two programs that aim to grow and diversify the physician workforce and invest in the state’s underserved areas, according to Lupe Alonzo-Diaz, CEO and president of PHC.

CalMedForce gives annual grants to fund new residency positions at graduate medical education (GME) programs throughout the state. The goal, Ms. Alonzo-Diaz said, is to expand the physician training pool. Funds were generated by Proposition 56, which was passed in 2016. The legislation generates tax on tobacco products. To date, GME programs have received more than $112 million to retain and expand primary care GME programs.

A second program, CalHealthCares, also funded by Proposition 56, offers a loan repayment program of up to $300,000 for physicians who meet certain criteria. “We are incentivizing young physicians and dentists to practice in Medi-Cal communities,” Ms. Alonzo-Diaz said, referring to the state’s Medicaid program. Clinicians must have graduated within the past 5 years (since Jan. 1, 2018) or will be graduating from a residency or fellowship program no later than June 30, 2023. Dentists applying for the practice support grant must have graduated from dental school or residency program within the past 15 years (since Jan. 1, 2008).

In exchange for the loan repayment, the health care providers are asked to commit to 5 years of service in the underserved community. So far, about 800 providers are part of the program, she said. According to Ms. Alonzo-Diaz, the average educational debt for health care providers in California is $315,000 to $350,000. That is as much as $100,000 above the national average.

What else is needed? Shannan Velayas, a spokesperson for the California Medical Association, said the state should invest in the Medi-Cal system to improve “meaningful access” to health care services and to expand loan repayment and residency programs like CalHealthCares and CalMedForce.

“Workforce shortages are not a reason to sacrifice quality of care or compromise patient safety but do warrant additional investment to increase access to medical providers working within their scope of practice,” Ms. Velayas said.
 

Widening scopes

Efforts are also underway to expand the scope of practice for nurse-practitioners, certified nurse-midwives, and physician assistants. Triggering these efforts has been the fallout and expected consequences of the overturning of Roe v. Wade, removing the federal right to abortion care.

Effective January 2023, trained and qualified nurse-practitioners and certified nurse-midwives in California can perform first-trimester abortions without a doctor’s supervision. Toni Atkins (D-San Diego), now president pro tempore of the California State Senate, authored the bill, SB1375. The measure builds on a 2013 law she spearheaded that allowed certain advanced-practice providers to perform first-trimester abortions with physician supervision.

On Feb. 13, Ms. Atkins introduced SB385, which gives physician assistants the same ability to become qualified in abortion care.

Ms. Atkins expressed confidence that teamwork would prevail in the efforts to have enough providers in the state. “One of the biggest lessons I learned working at a women’s health clinic [prior to her assuming her legislative positions] is that providers put their patients above all else, whether they are doctors, registered nurses, nurse practitioners, certified nurse-midwives, or physician assistants,” she said. “Everyone is on the same team when it comes to breaking down barriers and ensuring all Californians get the care they need without delay.”

Will other states follow suit? “This is pure speculation, but I believe states in which the political leadership supports abortion rights may see the California Reproductive Service Corps and the changes to scope-of-practice laws that allow specially trained CNMs, NPs, and PAs to provide abortions as a model for preserving access to abortion in their states,” Dr. Coffman said.

However, she said, “other states are less likely to view CalMedForce and CalHealthCares as models, because other states have had similar programs for many years, and some have historically invested larger shares of state budget resources into these programs, especially some rural states.”
 

Reports from the trenches

Laurie Love, DNP, RN, is a family nurse practitioner in Valencia and a clinical instructor and lecturer at the UCLA School of Nursing. When a patient becomes pregnant, she refers her to one of four local ob.gyns.

The working relationships she has with them, she said, “are extremely collaborative. There is no animosity or lack of respect because I don’t have an MD behind my name.”

One of those doctors is Dr. Ahdoot, who said he welcomes the expansion of scope of practice for non-MD health care providers. Some of his colleagues, he said, have tried to fight it, but many have come to the point of welcoming the help. “The consensus is you can’t practice without a nurse practitioner anymore,” Dr. Ahdoot told this news organization.

Expanding the scope of practice for other clinicians helps everyone, including patients, he said. He thinks about how the shortage affects them. “For patients, there is frustration,” he said. He said he often hears women saying they can’t schedule a pap smear for 3 months, or they can’t get a return call from their doctor.

Nalo Hamilton, PhD, an ob.gyn. nurse practitioner and associate professor at UCLA, said the physicians she interacts with support the expanded scope of practice. “Many are confused about details, about what it means and how it will impact them,” she said. “Those who understand it, yes, they agree with it. Doctors will simply have more health care providers who are able to do independent practice.” And she makes another point clear: “We won’t replace ob.gyns.”

None of the persons quoted in this story have disclosed any relevant financial relationships.

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

Three patients were waiting in a queue for their telemedicine visit. Four others were in exam rooms, waiting for their appointments. Another patient was on the phone, requesting a prescription renewal.

On a sunny Wednesday afternoon in February, David Ahdoot, MD, FACOG, an ob.gyn. in Burbank, Calif., about 10 miles north of downtown Los Angeles, knows he’ll be working late.

“Normally, we would be closed on Wednesday afternoon,” he said. That time would ordinarily be used to schedule surgeries, make dictation, and perform other tasks. But those were the old days, before the COVID-19 pandemic, before the ob.gyn. shortage got even worse, and before many of the other obstacles that make his practice more burdensome worsened.

Those Wednesday afternoon tasks must be done another time. “There are too many patients to see in the office,” said Dr. Ahdoot, who’s also an assistant clinical professor at UCLA. Because of the shortage of primary care physicians, he has taken on new patients, although he said he would like to focus on his existing ones.

Many of those existing patients have been coming to Dr. Ahdoot for years. “I love my job,” he said, and it shows.

His patient reviews online include the usual grumblings about waiting time and being rushed, but many, especially those from new parents, praise him as caring, compassionate, exceptional – the kind of doctor women trust to deliver their first baby and their next ones, then guide them through menopause and other issues.

The shortage of ob.gyns. in California, as elsewhere, is real, as Dr. Ahdoot’s day-to-day attests. The implications are in evidence well beyond his higher patient loads. Lately, Dr. Ahdoot said, the calls from headhunters seeking to fill positions for locum tenens have increased from twice a month to three times a day. Despite his love for his practice, he admits he thinks about stepping away. He is 56, 8 years short of the average retirement age for ob.gyns. nationally, according to a 2018 report.
 

Projected shortages

The shortage of primary care doctors, including ob.gyns., is nationwide. Dr. Ahdoot is one of many faces behind the statistics. According to a 2021 update from the U.S. Department of Health & Human Services, the number of ob.gyns. nationwide is expected to decrease 7% between 2018 and 2030, from 50,850 to 47,490. Meanwhile, demand is headed in the other direction – it is projected to rise 4%, from 50,850 to 52,660 ob.gyns. needed. The need for nurse-midwives, nurse-practitioners, and physician assistants who provide women’s health care is also expected to exceed the supply in coming years.

Some areas are harder hit. The Northeast is expected to have enough maternal health care providers to meet the current average level of care nationally but the West, Midwest, and South will not, according to HHS.

California will likely need an additional 4,700 primary care clinicians by 2025, according to projections by the HealthForce Center at the University of California, San Francisco.
 

Solutions in sight?

Efforts are increasing to make it easier or more appealing for ob.gyns. to practice, or remain in practice, in California. Some existing programs have received funding, while new initiatives to improve the situation are launching.

Some of these efforts and programs will be viewed as a model by some other states, said Janet Coffman, PhD, associate professor at UC San Francisco and a health policy expert who is familiar with new programs and established ones.

“I would say that California offers an example of a multifaceted approach to addressing the shortage of reproductive health providers in general and abortion providers in particular.”

The state has not sat idly in the face of dire predictions of shortfalls in the number of ob.gyns. Over the past decade, Dr. Coffman said, the legislature has “substantially” boosted funding for grants to support ob.gyn. residency programs through CalMedForce and the Song-Brown Healthcare Workforce Training Program. The result: an 18% increase in the number of residents entering the field over the past decade.

“These programs have also substantially increased funding for family medicine residency programs, which are important because family physicians are trained to provide preventive reproductive health services and manage low-risk deliveries,” she added. “Funding for midwifery, nurse midwifery, and nurse practitioner education has been more modest, which I find disappointing because they are qualified to provide many reproductive health services and are more likely to care for underserved populations.”

Other new programs and legislation are focused on expanding the scope of practice for nonphysician health care providers who care for women. Many of these measures are meant to ensure continued access to abortion services not just for California residents, who are guaranteed that right in the state constitution, but for the influx of women expected from states that limited or prohibited abortion after the overturn of Roe v. Wade.

Gavin Newsom, the state’s Democratic governor, has promoted California as a safe haven for women seeking abortions. In September, Gov. Newsom’s reelection campaign rented billboards in six states that have restrictive abortion laws with messages directing women to a website informing them “abortion is legal and protected in California.” The website includes a search function for women looking for providers – representing a further potential strain on the already stressed pool of clinicians. Each year, an estimated 8,000 to 16,100 more people are expected to travel to California for abortions, according to projections made in 2022 by the UCLA Center on Reproductive Health, Law, and Policy.

The questions are, will the efforts be enough to stall or reverse the shortage, and will the efforts to expand other health care providers’ scope of practice be met with cooperation or resistance by MDs?
 

Just launched: California reproductive health service corps

Brand new, as of January 2023, is the California Reproductive Health Service Corps, created by a bill Gov. Newsom signed into law last September. The program operates within the Department of Health Care Access and Information. Rajeena Victoria Bisla, a spokesperson for assemblywoman Cottie Petrie-Norris (D-Irvine), who authored the bill, said: “The Corps will be responsible for recruiting, training, and retaining a diverse workforce of health care professionals who will be part of reproductive health care teams assigned to work in underserved areas.”

The teams will include MDs as well as licensed midwives, nurses, physician’s assistants, doulas, and medical assistants. They will provide abortion care, contraception, perinatal care, gynecology services, and gender-affirming care, among other needs, Ms. Bisla said.

The California Medical Association’s philanthropic arm, Physicians for a Healthy California (PHC), has two programs that aim to grow and diversify the physician workforce and invest in the state’s underserved areas, according to Lupe Alonzo-Diaz, CEO and president of PHC.

CalMedForce gives annual grants to fund new residency positions at graduate medical education (GME) programs throughout the state. The goal, Ms. Alonzo-Diaz said, is to expand the physician training pool. Funds were generated by Proposition 56, which was passed in 2016. The legislation generates tax on tobacco products. To date, GME programs have received more than $112 million to retain and expand primary care GME programs.

A second program, CalHealthCares, also funded by Proposition 56, offers a loan repayment program of up to $300,000 for physicians who meet certain criteria. “We are incentivizing young physicians and dentists to practice in Medi-Cal communities,” Ms. Alonzo-Diaz said, referring to the state’s Medicaid program. Clinicians must have graduated within the past 5 years (since Jan. 1, 2018) or will be graduating from a residency or fellowship program no later than June 30, 2023. Dentists applying for the practice support grant must have graduated from dental school or residency program within the past 15 years (since Jan. 1, 2008).

In exchange for the loan repayment, the health care providers are asked to commit to 5 years of service in the underserved community. So far, about 800 providers are part of the program, she said. According to Ms. Alonzo-Diaz, the average educational debt for health care providers in California is $315,000 to $350,000. That is as much as $100,000 above the national average.

What else is needed? Shannan Velayas, a spokesperson for the California Medical Association, said the state should invest in the Medi-Cal system to improve “meaningful access” to health care services and to expand loan repayment and residency programs like CalHealthCares and CalMedForce.

“Workforce shortages are not a reason to sacrifice quality of care or compromise patient safety but do warrant additional investment to increase access to medical providers working within their scope of practice,” Ms. Velayas said.
 

Widening scopes

Efforts are also underway to expand the scope of practice for nurse-practitioners, certified nurse-midwives, and physician assistants. Triggering these efforts has been the fallout and expected consequences of the overturning of Roe v. Wade, removing the federal right to abortion care.

Effective January 2023, trained and qualified nurse-practitioners and certified nurse-midwives in California can perform first-trimester abortions without a doctor’s supervision. Toni Atkins (D-San Diego), now president pro tempore of the California State Senate, authored the bill, SB1375. The measure builds on a 2013 law she spearheaded that allowed certain advanced-practice providers to perform first-trimester abortions with physician supervision.

On Feb. 13, Ms. Atkins introduced SB385, which gives physician assistants the same ability to become qualified in abortion care.

Ms. Atkins expressed confidence that teamwork would prevail in the efforts to have enough providers in the state. “One of the biggest lessons I learned working at a women’s health clinic [prior to her assuming her legislative positions] is that providers put their patients above all else, whether they are doctors, registered nurses, nurse practitioners, certified nurse-midwives, or physician assistants,” she said. “Everyone is on the same team when it comes to breaking down barriers and ensuring all Californians get the care they need without delay.”

Will other states follow suit? “This is pure speculation, but I believe states in which the political leadership supports abortion rights may see the California Reproductive Service Corps and the changes to scope-of-practice laws that allow specially trained CNMs, NPs, and PAs to provide abortions as a model for preserving access to abortion in their states,” Dr. Coffman said.

However, she said, “other states are less likely to view CalMedForce and CalHealthCares as models, because other states have had similar programs for many years, and some have historically invested larger shares of state budget resources into these programs, especially some rural states.”
 

Reports from the trenches

Laurie Love, DNP, RN, is a family nurse practitioner in Valencia and a clinical instructor and lecturer at the UCLA School of Nursing. When a patient becomes pregnant, she refers her to one of four local ob.gyns.

The working relationships she has with them, she said, “are extremely collaborative. There is no animosity or lack of respect because I don’t have an MD behind my name.”

One of those doctors is Dr. Ahdoot, who said he welcomes the expansion of scope of practice for non-MD health care providers. Some of his colleagues, he said, have tried to fight it, but many have come to the point of welcoming the help. “The consensus is you can’t practice without a nurse practitioner anymore,” Dr. Ahdoot told this news organization.

Expanding the scope of practice for other clinicians helps everyone, including patients, he said. He thinks about how the shortage affects them. “For patients, there is frustration,” he said. He said he often hears women saying they can’t schedule a pap smear for 3 months, or they can’t get a return call from their doctor.

Nalo Hamilton, PhD, an ob.gyn. nurse practitioner and associate professor at UCLA, said the physicians she interacts with support the expanded scope of practice. “Many are confused about details, about what it means and how it will impact them,” she said. “Those who understand it, yes, they agree with it. Doctors will simply have more health care providers who are able to do independent practice.” And she makes another point clear: “We won’t replace ob.gyns.”

None of the persons quoted in this story have disclosed any relevant financial relationships.

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

Three patients were waiting in a queue for their telemedicine visit. Four others were in exam rooms, waiting for their appointments. Another patient was on the phone, requesting a prescription renewal.

On a sunny Wednesday afternoon in February, David Ahdoot, MD, FACOG, an ob.gyn. in Burbank, Calif., about 10 miles north of downtown Los Angeles, knows he’ll be working late.

“Normally, we would be closed on Wednesday afternoon,” he said. That time would ordinarily be used to schedule surgeries, make dictation, and perform other tasks. But those were the old days, before the COVID-19 pandemic, before the ob.gyn. shortage got even worse, and before many of the other obstacles that make his practice more burdensome worsened.

Those Wednesday afternoon tasks must be done another time. “There are too many patients to see in the office,” said Dr. Ahdoot, who’s also an assistant clinical professor at UCLA. Because of the shortage of primary care physicians, he has taken on new patients, although he said he would like to focus on his existing ones.

Many of those existing patients have been coming to Dr. Ahdoot for years. “I love my job,” he said, and it shows.

His patient reviews online include the usual grumblings about waiting time and being rushed, but many, especially those from new parents, praise him as caring, compassionate, exceptional – the kind of doctor women trust to deliver their first baby and their next ones, then guide them through menopause and other issues.

The shortage of ob.gyns. in California, as elsewhere, is real, as Dr. Ahdoot’s day-to-day attests. The implications are in evidence well beyond his higher patient loads. Lately, Dr. Ahdoot said, the calls from headhunters seeking to fill positions for locum tenens have increased from twice a month to three times a day. Despite his love for his practice, he admits he thinks about stepping away. He is 56, 8 years short of the average retirement age for ob.gyns. nationally, according to a 2018 report.
 

Projected shortages

The shortage of primary care doctors, including ob.gyns., is nationwide. Dr. Ahdoot is one of many faces behind the statistics. According to a 2021 update from the U.S. Department of Health & Human Services, the number of ob.gyns. nationwide is expected to decrease 7% between 2018 and 2030, from 50,850 to 47,490. Meanwhile, demand is headed in the other direction – it is projected to rise 4%, from 50,850 to 52,660 ob.gyns. needed. The need for nurse-midwives, nurse-practitioners, and physician assistants who provide women’s health care is also expected to exceed the supply in coming years.

Some areas are harder hit. The Northeast is expected to have enough maternal health care providers to meet the current average level of care nationally but the West, Midwest, and South will not, according to HHS.

California will likely need an additional 4,700 primary care clinicians by 2025, according to projections by the HealthForce Center at the University of California, San Francisco.
 

Solutions in sight?

Efforts are increasing to make it easier or more appealing for ob.gyns. to practice, or remain in practice, in California. Some existing programs have received funding, while new initiatives to improve the situation are launching.

Some of these efforts and programs will be viewed as a model by some other states, said Janet Coffman, PhD, associate professor at UC San Francisco and a health policy expert who is familiar with new programs and established ones.

“I would say that California offers an example of a multifaceted approach to addressing the shortage of reproductive health providers in general and abortion providers in particular.”

The state has not sat idly in the face of dire predictions of shortfalls in the number of ob.gyns. Over the past decade, Dr. Coffman said, the legislature has “substantially” boosted funding for grants to support ob.gyn. residency programs through CalMedForce and the Song-Brown Healthcare Workforce Training Program. The result: an 18% increase in the number of residents entering the field over the past decade.

“These programs have also substantially increased funding for family medicine residency programs, which are important because family physicians are trained to provide preventive reproductive health services and manage low-risk deliveries,” she added. “Funding for midwifery, nurse midwifery, and nurse practitioner education has been more modest, which I find disappointing because they are qualified to provide many reproductive health services and are more likely to care for underserved populations.”

Other new programs and legislation are focused on expanding the scope of practice for nonphysician health care providers who care for women. Many of these measures are meant to ensure continued access to abortion services not just for California residents, who are guaranteed that right in the state constitution, but for the influx of women expected from states that limited or prohibited abortion after the overturn of Roe v. Wade.

Gavin Newsom, the state’s Democratic governor, has promoted California as a safe haven for women seeking abortions. In September, Gov. Newsom’s reelection campaign rented billboards in six states that have restrictive abortion laws with messages directing women to a website informing them “abortion is legal and protected in California.” The website includes a search function for women looking for providers – representing a further potential strain on the already stressed pool of clinicians. Each year, an estimated 8,000 to 16,100 more people are expected to travel to California for abortions, according to projections made in 2022 by the UCLA Center on Reproductive Health, Law, and Policy.

The questions are, will the efforts be enough to stall or reverse the shortage, and will the efforts to expand other health care providers’ scope of practice be met with cooperation or resistance by MDs?
 

Just launched: California reproductive health service corps

Brand new, as of January 2023, is the California Reproductive Health Service Corps, created by a bill Gov. Newsom signed into law last September. The program operates within the Department of Health Care Access and Information. Rajeena Victoria Bisla, a spokesperson for assemblywoman Cottie Petrie-Norris (D-Irvine), who authored the bill, said: “The Corps will be responsible for recruiting, training, and retaining a diverse workforce of health care professionals who will be part of reproductive health care teams assigned to work in underserved areas.”

The teams will include MDs as well as licensed midwives, nurses, physician’s assistants, doulas, and medical assistants. They will provide abortion care, contraception, perinatal care, gynecology services, and gender-affirming care, among other needs, Ms. Bisla said.

The California Medical Association’s philanthropic arm, Physicians for a Healthy California (PHC), has two programs that aim to grow and diversify the physician workforce and invest in the state’s underserved areas, according to Lupe Alonzo-Diaz, CEO and president of PHC.

CalMedForce gives annual grants to fund new residency positions at graduate medical education (GME) programs throughout the state. The goal, Ms. Alonzo-Diaz said, is to expand the physician training pool. Funds were generated by Proposition 56, which was passed in 2016. The legislation generates tax on tobacco products. To date, GME programs have received more than $112 million to retain and expand primary care GME programs.

A second program, CalHealthCares, also funded by Proposition 56, offers a loan repayment program of up to $300,000 for physicians who meet certain criteria. “We are incentivizing young physicians and dentists to practice in Medi-Cal communities,” Ms. Alonzo-Diaz said, referring to the state’s Medicaid program. Clinicians must have graduated within the past 5 years (since Jan. 1, 2018) or will be graduating from a residency or fellowship program no later than June 30, 2023. Dentists applying for the practice support grant must have graduated from dental school or residency program within the past 15 years (since Jan. 1, 2008).

In exchange for the loan repayment, the health care providers are asked to commit to 5 years of service in the underserved community. So far, about 800 providers are part of the program, she said. According to Ms. Alonzo-Diaz, the average educational debt for health care providers in California is $315,000 to $350,000. That is as much as $100,000 above the national average.

What else is needed? Shannan Velayas, a spokesperson for the California Medical Association, said the state should invest in the Medi-Cal system to improve “meaningful access” to health care services and to expand loan repayment and residency programs like CalHealthCares and CalMedForce.

“Workforce shortages are not a reason to sacrifice quality of care or compromise patient safety but do warrant additional investment to increase access to medical providers working within their scope of practice,” Ms. Velayas said.
 

Widening scopes

Efforts are also underway to expand the scope of practice for nurse-practitioners, certified nurse-midwives, and physician assistants. Triggering these efforts has been the fallout and expected consequences of the overturning of Roe v. Wade, removing the federal right to abortion care.

Effective January 2023, trained and qualified nurse-practitioners and certified nurse-midwives in California can perform first-trimester abortions without a doctor’s supervision. Toni Atkins (D-San Diego), now president pro tempore of the California State Senate, authored the bill, SB1375. The measure builds on a 2013 law she spearheaded that allowed certain advanced-practice providers to perform first-trimester abortions with physician supervision.

On Feb. 13, Ms. Atkins introduced SB385, which gives physician assistants the same ability to become qualified in abortion care.

Ms. Atkins expressed confidence that teamwork would prevail in the efforts to have enough providers in the state. “One of the biggest lessons I learned working at a women’s health clinic [prior to her assuming her legislative positions] is that providers put their patients above all else, whether they are doctors, registered nurses, nurse practitioners, certified nurse-midwives, or physician assistants,” she said. “Everyone is on the same team when it comes to breaking down barriers and ensuring all Californians get the care they need without delay.”

Will other states follow suit? “This is pure speculation, but I believe states in which the political leadership supports abortion rights may see the California Reproductive Service Corps and the changes to scope-of-practice laws that allow specially trained CNMs, NPs, and PAs to provide abortions as a model for preserving access to abortion in their states,” Dr. Coffman said.

However, she said, “other states are less likely to view CalMedForce and CalHealthCares as models, because other states have had similar programs for many years, and some have historically invested larger shares of state budget resources into these programs, especially some rural states.”
 

Reports from the trenches

Laurie Love, DNP, RN, is a family nurse practitioner in Valencia and a clinical instructor and lecturer at the UCLA School of Nursing. When a patient becomes pregnant, she refers her to one of four local ob.gyns.

The working relationships she has with them, she said, “are extremely collaborative. There is no animosity or lack of respect because I don’t have an MD behind my name.”

One of those doctors is Dr. Ahdoot, who said he welcomes the expansion of scope of practice for non-MD health care providers. Some of his colleagues, he said, have tried to fight it, but many have come to the point of welcoming the help. “The consensus is you can’t practice without a nurse practitioner anymore,” Dr. Ahdoot told this news organization.

Expanding the scope of practice for other clinicians helps everyone, including patients, he said. He thinks about how the shortage affects them. “For patients, there is frustration,” he said. He said he often hears women saying they can’t schedule a pap smear for 3 months, or they can’t get a return call from their doctor.

Nalo Hamilton, PhD, an ob.gyn. nurse practitioner and associate professor at UCLA, said the physicians she interacts with support the expanded scope of practice. “Many are confused about details, about what it means and how it will impact them,” she said. “Those who understand it, yes, they agree with it. Doctors will simply have more health care providers who are able to do independent practice.” And she makes another point clear: “We won’t replace ob.gyns.”

None of the persons quoted in this story have disclosed any relevant financial relationships.

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

Introduction: The preoperative evaluation for endometriosis – more than meets the eye

It is well known that it often takes 6-10 years for endometriosis to be diagnosed in patients who have the disease, depending on where the patient lives. I certainly am not surprised. During my residency at Parkland Memorial Hospital, if a patient had chronic pelvic pain and no fibroids, her diagnosis was usually pelvic inflammatory disease. Later, during my fellowship in reproductive endocrinology at the University of Pennsylvania, the diagnosis became endometriosis.

As I gained more interest and expertise in the treatment of endometriosis, I became aware of several articles concluding that if a woman sought treatment for chronic pelvic pain with an internist, the diagnosis would be irritable bowel syndrome (IBS); with a urologist, it would be interstitial cystitis; and with a gynecologist, endometriosis. Moreover, there is an increased propensity for IBS and IC in patients with endometriosis. There also is an increased risk of small intestine bacterial overgrowth (SIBO), as noted by our guest author for this latest installment of the Master Class in Gynecologic Surgery, Iris Orbuch, MD.

Like our guest author, I have also noted increased risk of pelvic floor myalgia. Dr. Orbuch clearly outlines why this occurs. In fact, we can now understand why many patients have multiple pelvic pain–inducing issues compounding their pain secondary to endometriosis and leading to remodeling of the central nervous system. Therefore, it certainly makes sense to follow Dr. Orbuch’s recommendation for a multidisciplinary pre- and postsurgical approach “to downregulate the pain generators.”

Dr. Orbuch is a minimally invasive gynecologic surgeon in Los Angeles who specializes in the treatment of patients diagnosed with endometriosis. Dr. Orbuch serves on the Board of Directors of the Foundation of the American Association of Gynecologic Laparoscopists and has served as the chair of the AAGL’s Special Interest Group on Endometriosis and Reproductive Surgery. She is the coauthor of the book “Beating Endo – How to Reclaim Your Life From Endometriosis” (New York: HarperCollins; 2019). The book is written for patients but addresses many issues discussed in this installment of the Master Class in Gynecologic Surgery.

Dr. Miller, MD, FACOG, is professor of obstetrics and gynecology, department of clinical sciences, Rosalind Franklin University of Medicine and Science, North Chicago. He has no conflicts of interest to report.

For optimal surgical outcomes, and to help our patients recover from years of this inflammatory, systemic disease, we must treat our patients holistically and work to downregulate their pain as much as possible before excision surgery. I work with patients a few months prior to surgery, often for 4-5 months, during which time they not only see me for informative follow-ups, but also pelvic floor physical therapists, gastroenterologists, mental health professionals, integrative nutritionists, and physiatrists or pain specialists, depending on their needs.¹

By identifying coexisting conditions in an initial consult and employing a presurgical multidisciplinary approach to downregulate the pain generators, my patients recover well from excision surgery, with greater and faster relief from pain, compared with those using standard approaches, and with little to no use of opioids.

At a minimum, given the unfortunate time constraints and productivity demands of working within health systems – and considering that surgeries are often scheduled a couple of months out – the surgeon could ensure that patients are engaged in at least 6-8 weeks of pelvic floor physical therapy before surgery to sufficiently lengthen the pelvic muscles and loosen surrounding fascia.

Short, tight pelvic floor muscles are almost universal in patients with delayed diagnosis of endometriosis and are significant generators of pain.
 

Appreciating sequelae of diagnostic delay

After my fellowship in advanced laparoscopic and pelvic surgery with Harry Reich, MD, and C. Y. Liu, MD, pioneers of endometriosis excision surgery, and as I did my residency in the early 2000s, I noticed puzzlement in the literature about why some patients still had lasting pain after thorough excision.

I didn’t doubt the efficacy of excision. It is the cornerstone of treatment, and at least one randomized double-blind trial² and a systematic review and meta-analysis³ have demonstrated its superior efficacy over ablation in symptom reduction. What I did doubt was any presumption that surgery alone was enough. I knew there was more to healing when a disease process wreaks havoc on the body for more than a decade and that there were other generators of pain in addition to the endometriosis implants themselves.

As I began to focus on endometriosis in my own surgical practice, I strove to detect and treat endometriosis in teens. But in those patients with longstanding disease, I recognized patterns and began to more fully appreciate the systemic sequelae of endometriosis.

To cope with dysmenorrhea, patients curl up and assume a fetal position, tensing the abdominal muscles, inner thigh muscles, and pelvic floor muscles. Over time, these muscles come to maintain a short, tight, and painful state. (Hence the need for physical therapy to undo this decade-long pattern.)

Endometriosis implants on or near the gastrointestinal tract tug on fascia and muscles and commonly cause constipation, leading women to further overwork the pelvic floor muscles. In the case of diarrhea-predominant dysfunction, our patients squeeze pelvic floor muscles to prevent leakage. And in the case of urinary urgency, they squeeze muscles to release urine that isn’t really there.

As the chronic inflammation of the disease grows, and as pain worsens, the patient is increasingly in sympathetic overdrive (also known as ”fight or flight”), as opposed to a parasympathetic state (also known as “rest and digest”). The bowel’s motility slows, allowing the bacteria of the small intestine to grow beyond what is normal, leading to SIBO, a condition increasingly recognized by gastroenterologists and others that can impede nutrient absorption and cause bloat and pain and exacerbate constipation and diarrhea.

Key to my conceptualization of pain was a review published in 2011 by Pam Stratton, MD, of the National Institutes of Health, and Karen J. Berkley, PhD, then of Florida State University, on chronic pain and endometriosis.⁴ They detailed how endometriotic lesions can develop their own nerve supply that interacts directly and in a two-way fashion with the CNS – and how the lesions can engage the nervous system in ways that create comorbid conditions and pain that becomes “independent of the disease itself.”

Sensitized peripheral nerve fibers innervating a deeply infiltrating lesion on the left uterosacral ligament, for instance, can sensitize neurons in the spinal sacral segment. Branches of these nerve fibers can extend to other segments of the spinal cord, and, once sensitized themselves, turn on neurons in these other segments. There is a resultant remodeling of the central nervous system, in essence, and what is called “remote central sensitization.” The CNS becomes independent from peripheral neural processes.

I now explain to both patients and physicians that those who have had endometriosis for years have had an enduring “hand on the stove,” with a persistent signal to the CNS. Tight muscles are a hand on the stove, painful bladder syndrome is another hand on the stove, and SIBO is yet another. So are anxiety and depression.

The CNS becomes so upregulated and overloaded that messages branch out through the spinal cord to other available pathways and to other organs, muscles, and nerves. The CNS also starts firing on its own – and once it becomes its own pain generator, taking one hand off the stove (for instance, excising implants) while leaving multiple other hands on the hot stove won’t remove all pain. We must downregulate the CNS more broadly.

As I began addressing pain generators and instigators of CNS sensitization – and waiting for excision surgery until the CNS had sufficiently cooled – I saw that my patients had a better chance of more significant and lasting pain relief.
 

Pearls for a multimodal approach

My initial physical exam includes an assessment of the pelvic floor for overly tight musculature. An abdominal exam will usually reveal whether there is asymmetry of the abdominal wall muscles, which typically informs me of the likelihood of tightness and pulling on either side of the pelvic anatomy. On the internal exam, then, the pelvic floor muscles can be palpated and assessed. These findings will guide my referrals and my discussions with patients about the value of pelvic floor physical therapy. The cervix should be in the midline of the vagina – equidistant from the left and right vaginal fornices. If the cervix is pulled away from this midline, and a palpation of a thickened uterosacral ligament reproduces pain, endometriosis is 90% likely.

Patients who report significant “burning” pain that’s suggestive of neuropathic pain should be referred to a physical medicine rehabilitation physician or a pain specialist who can help downregulate their CNS. And patients who have symptoms of depression, anxiety disorders (including obsessive-compulsive disorder), or posttraumatic stress disorder should be referred to pain therapists, psychologists, or other mental health professionals, preferably well before surgery. I will also often discuss mindfulness practices and give my patients “meditation challenges” to achieve during the presurgical phase.

Additional points of emphasis about a multidisciplinary, multimodal approach include:

Advanced pelvic floor therapy: Therapists with specialized training in pelvic health and manual therapy utilize a range of techniques and modalities to release tension in affected muscles, fascia, nerves, and bone, and in doing so, they help to downregulate the CNS. Myofascial release, myofascial trigger point release, neural mobilization, and visceral mobilization are among these techniques. In addition to using manual therapy, many of these therapists may also employ neuromuscular reeducation and other techniques that will be helpful for the longer term.

It is important to identify physical therapists who have training in this approach; women with endometriosis often have a history of treatment by physical therapists whose focus is on incontinence and muscle strengthening (that is, Kegel exercises), which is the opposite of what endometriosis patients need.

Treating SIBO: Symptoms commonly associated with SIBO often overlap with symptoms of irritable bowel syndrome (IBS) – namely constipation, diarrhea (or both), and bloating. Indeed, many patients with undiagnosed endometriosis have been diagnosed with IBS. I send every patient who has one of these symptoms for SIBO breath testing, which utilizes carbohydrate substrates (glucose or lactulose) and measures hydrogen and/or methane in the breath.

SIBO is typically treated with rifampin, which stays in the small bowel and will not negatively affect beneficial bacteria, with or without neomycin. Gastroenterologists with more integrative practices also consider the use of herbals in addition to – or instead of – antibiotics. It can sometimes take months or a couple of years to correct SIBO, depending on how long the patient has been affected, but with presurgical diagnosis and a start on treatment, we can remove or at least tone down another instigator of CNS sensitization.

I estimate that 80% of my patients have tested positive for SIBO. Notably, in a testament to the systemic nature of endometriosis, a study published in 2009 of 355 women undergoing operative laparoscopy for suspected endometriosis found that 90% had gastrointestinal symptoms, but only 7.6% of the vast majority whose endometriosis was confirmed were found to have endometrial implants on the bowel itself.⁵

Addressing bladder issues: I routinely administer the PUF (Pain, Urgency, Frequency) questionnaire as part of my intake package and follow it up with conversation. For just about every patient with painful bladder syndrome, pelvic floor physical therapy in combination with a low-acid, low-potassium diet will work effectively together to reduce symptoms and pain. The IC Network offers a helpful food list, and patients can be counseled to choose foods that are also anti-inflammatory. When referrals to a urologist for bladder instillations are possible, these can be helpful as well.

Our communication with patients

Our patients need to have their symptoms and pain validated and to understand why we’re recommending these measures before surgery. Some education is necessary. Few patients will go to an integrative nutritionist, for example, if we just write a referral without explaining how years of inflammation and disruption in the gut can affect the whole body – including mental health – and that it can be corrected over time.

Also necessary is an appreciation of the fact that patients with delayed diagnoses have lived with gastrointestinal and other symptoms and patterns for so long – and often have mothers whose endometriosis caused similar symptoms – that some of their own experiences can seem almost “normal.” A patient whose mother had bowel movements every 7 days may think that 4-5 day intervals are acceptable, for instance. This means we have to carefully consider how we ask our questions.

I always ask my patients as we’re going into surgery, what percentage better are you? I’ve long aimed for at least 30% improvement, but most of the time, with pelvic floor therapy and as many other pain-generator–focused measures as possible, we’re getting them 70% better.

Excision surgery will remove the inflammation that has helped fuel the SIBO and other coconditions. Then, everything done to prepare the body must continue for some time. Certain practices, such as eating an anti-inflammatory diet, should be lifelong.

One day, it is hoped, a pediatrician or other physician will suspect endometriosis early on. The patient will see the surgeon within several months of the onset of pain, and we won’t need to unravel layers of pain generation and CNS upregulation before operating. But until this happens and we shorten the diagnostic delay, we must consider the benefits of presurgical preparation.
 

References

1. Orbuch I, Stein A. Beating Endo: How to Reclaim Your Life From Endometriosis. (New York: HarperCollins, 2019).

2. Healey M et al. J Minim Invasive Gynecol. 2014;21(6):999-1004.

3. Pundir J et al. J Minim Invasive Gynecol. 2017;24(5):747-56.

4. Stratton P, Berkley KJ. Hum Repro Update. 2011;17(3):327-46.

5. Maroun P et al. Aust N Z J Obstet Gynaecol. 2009;49(4):411-4.

Dr. Orbuch is a minimally invasive gynecologic surgeon in Los Angeles who specializes in endometriosis. She has no conflicts of interest to report.

Introduction: The preoperative evaluation for endometriosis – more than meets the eye

It is well known that it often takes 6-10 years for endometriosis to be diagnosed in patients who have the disease, depending on where the patient lives. I certainly am not surprised. During my residency at Parkland Memorial Hospital, if a patient had chronic pelvic pain and no fibroids, her diagnosis was usually pelvic inflammatory disease. Later, during my fellowship in reproductive endocrinology at the University of Pennsylvania, the diagnosis became endometriosis.

As I gained more interest and expertise in the treatment of endometriosis, I became aware of several articles concluding that if a woman sought treatment for chronic pelvic pain with an internist, the diagnosis would be irritable bowel syndrome (IBS); with a urologist, it would be interstitial cystitis; and with a gynecologist, endometriosis. Moreover, there is an increased propensity for IBS and IC in patients with endometriosis. There also is an increased risk of small intestine bacterial overgrowth (SIBO), as noted by our guest author for this latest installment of the Master Class in Gynecologic Surgery, Iris Orbuch, MD.

Like our guest author, I have also noted increased risk of pelvic floor myalgia. Dr. Orbuch clearly outlines why this occurs. In fact, we can now understand why many patients have multiple pelvic pain–inducing issues compounding their pain secondary to endometriosis and leading to remodeling of the central nervous system. Therefore, it certainly makes sense to follow Dr. Orbuch’s recommendation for a multidisciplinary pre- and postsurgical approach “to downregulate the pain generators.”

Dr. Orbuch is a minimally invasive gynecologic surgeon in Los Angeles who specializes in the treatment of patients diagnosed with endometriosis. Dr. Orbuch serves on the Board of Directors of the Foundation of the American Association of Gynecologic Laparoscopists and has served as the chair of the AAGL’s Special Interest Group on Endometriosis and Reproductive Surgery. She is the coauthor of the book “Beating Endo – How to Reclaim Your Life From Endometriosis” (New York: HarperCollins; 2019). The book is written for patients but addresses many issues discussed in this installment of the Master Class in Gynecologic Surgery.

Dr. Miller, MD, FACOG, is professor of obstetrics and gynecology, department of clinical sciences, Rosalind Franklin University of Medicine and Science, North Chicago. He has no conflicts of interest to report.

For optimal surgical outcomes, and to help our patients recover from years of this inflammatory, systemic disease, we must treat our patients holistically and work to downregulate their pain as much as possible before excision surgery. I work with patients a few months prior to surgery, often for 4-5 months, during which time they not only see me for informative follow-ups, but also pelvic floor physical therapists, gastroenterologists, mental health professionals, integrative nutritionists, and physiatrists or pain specialists, depending on their needs.¹

By identifying coexisting conditions in an initial consult and employing a presurgical multidisciplinary approach to downregulate the pain generators, my patients recover well from excision surgery, with greater and faster relief from pain, compared with those using standard approaches, and with little to no use of opioids.

At a minimum, given the unfortunate time constraints and productivity demands of working within health systems – and considering that surgeries are often scheduled a couple of months out – the surgeon could ensure that patients are engaged in at least 6-8 weeks of pelvic floor physical therapy before surgery to sufficiently lengthen the pelvic muscles and loosen surrounding fascia.

Short, tight pelvic floor muscles are almost universal in patients with delayed diagnosis of endometriosis and are significant generators of pain.
 

Appreciating sequelae of diagnostic delay

After my fellowship in advanced laparoscopic and pelvic surgery with Harry Reich, MD, and C. Y. Liu, MD, pioneers of endometriosis excision surgery, and as I did my residency in the early 2000s, I noticed puzzlement in the literature about why some patients still had lasting pain after thorough excision.

I didn’t doubt the efficacy of excision. It is the cornerstone of treatment, and at least one randomized double-blind trial² and a systematic review and meta-analysis³ have demonstrated its superior efficacy over ablation in symptom reduction. What I did doubt was any presumption that surgery alone was enough. I knew there was more to healing when a disease process wreaks havoc on the body for more than a decade and that there were other generators of pain in addition to the endometriosis implants themselves.

As I began to focus on endometriosis in my own surgical practice, I strove to detect and treat endometriosis in teens. But in those patients with longstanding disease, I recognized patterns and began to more fully appreciate the systemic sequelae of endometriosis.

To cope with dysmenorrhea, patients curl up and assume a fetal position, tensing the abdominal muscles, inner thigh muscles, and pelvic floor muscles. Over time, these muscles come to maintain a short, tight, and painful state. (Hence the need for physical therapy to undo this decade-long pattern.)

Endometriosis implants on or near the gastrointestinal tract tug on fascia and muscles and commonly cause constipation, leading women to further overwork the pelvic floor muscles. In the case of diarrhea-predominant dysfunction, our patients squeeze pelvic floor muscles to prevent leakage. And in the case of urinary urgency, they squeeze muscles to release urine that isn’t really there.

As the chronic inflammation of the disease grows, and as pain worsens, the patient is increasingly in sympathetic overdrive (also known as ”fight or flight”), as opposed to a parasympathetic state (also known as “rest and digest”). The bowel’s motility slows, allowing the bacteria of the small intestine to grow beyond what is normal, leading to SIBO, a condition increasingly recognized by gastroenterologists and others that can impede nutrient absorption and cause bloat and pain and exacerbate constipation and diarrhea.

Key to my conceptualization of pain was a review published in 2011 by Pam Stratton, MD, of the National Institutes of Health, and Karen J. Berkley, PhD, then of Florida State University, on chronic pain and endometriosis.⁴ They detailed how endometriotic lesions can develop their own nerve supply that interacts directly and in a two-way fashion with the CNS – and how the lesions can engage the nervous system in ways that create comorbid conditions and pain that becomes “independent of the disease itself.”

Sensitized peripheral nerve fibers innervating a deeply infiltrating lesion on the left uterosacral ligament, for instance, can sensitize neurons in the spinal sacral segment. Branches of these nerve fibers can extend to other segments of the spinal cord, and, once sensitized themselves, turn on neurons in these other segments. There is a resultant remodeling of the central nervous system, in essence, and what is called “remote central sensitization.” The CNS becomes independent from peripheral neural processes.

I now explain to both patients and physicians that those who have had endometriosis for years have had an enduring “hand on the stove,” with a persistent signal to the CNS. Tight muscles are a hand on the stove, painful bladder syndrome is another hand on the stove, and SIBO is yet another. So are anxiety and depression.

The CNS becomes so upregulated and overloaded that messages branch out through the spinal cord to other available pathways and to other organs, muscles, and nerves. The CNS also starts firing on its own – and once it becomes its own pain generator, taking one hand off the stove (for instance, excising implants) while leaving multiple other hands on the hot stove won’t remove all pain. We must downregulate the CNS more broadly.

As I began addressing pain generators and instigators of CNS sensitization – and waiting for excision surgery until the CNS had sufficiently cooled – I saw that my patients had a better chance of more significant and lasting pain relief.
 

Pearls for a multimodal approach

My initial physical exam includes an assessment of the pelvic floor for overly tight musculature. An abdominal exam will usually reveal whether there is asymmetry of the abdominal wall muscles, which typically informs me of the likelihood of tightness and pulling on either side of the pelvic anatomy. On the internal exam, then, the pelvic floor muscles can be palpated and assessed. These findings will guide my referrals and my discussions with patients about the value of pelvic floor physical therapy. The cervix should be in the midline of the vagina – equidistant from the left and right vaginal fornices. If the cervix is pulled away from this midline, and a palpation of a thickened uterosacral ligament reproduces pain, endometriosis is 90% likely.

Patients who report significant “burning” pain that’s suggestive of neuropathic pain should be referred to a physical medicine rehabilitation physician or a pain specialist who can help downregulate their CNS. And patients who have symptoms of depression, anxiety disorders (including obsessive-compulsive disorder), or posttraumatic stress disorder should be referred to pain therapists, psychologists, or other mental health professionals, preferably well before surgery. I will also often discuss mindfulness practices and give my patients “meditation challenges” to achieve during the presurgical phase.

Additional points of emphasis about a multidisciplinary, multimodal approach include:

Advanced pelvic floor therapy: Therapists with specialized training in pelvic health and manual therapy utilize a range of techniques and modalities to release tension in affected muscles, fascia, nerves, and bone, and in doing so, they help to downregulate the CNS. Myofascial release, myofascial trigger point release, neural mobilization, and visceral mobilization are among these techniques. In addition to using manual therapy, many of these therapists may also employ neuromuscular reeducation and other techniques that will be helpful for the longer term.

It is important to identify physical therapists who have training in this approach; women with endometriosis often have a history of treatment by physical therapists whose focus is on incontinence and muscle strengthening (that is, Kegel exercises), which is the opposite of what endometriosis patients need.

Treating SIBO: Symptoms commonly associated with SIBO often overlap with symptoms of irritable bowel syndrome (IBS) – namely constipation, diarrhea (or both), and bloating. Indeed, many patients with undiagnosed endometriosis have been diagnosed with IBS. I send every patient who has one of these symptoms for SIBO breath testing, which utilizes carbohydrate substrates (glucose or lactulose) and measures hydrogen and/or methane in the breath.

SIBO is typically treated with rifampin, which stays in the small bowel and will not negatively affect beneficial bacteria, with or without neomycin. Gastroenterologists with more integrative practices also consider the use of herbals in addition to – or instead of – antibiotics. It can sometimes take months or a couple of years to correct SIBO, depending on how long the patient has been affected, but with presurgical diagnosis and a start on treatment, we can remove or at least tone down another instigator of CNS sensitization.

I estimate that 80% of my patients have tested positive for SIBO. Notably, in a testament to the systemic nature of endometriosis, a study published in 2009 of 355 women undergoing operative laparoscopy for suspected endometriosis found that 90% had gastrointestinal symptoms, but only 7.6% of the vast majority whose endometriosis was confirmed were found to have endometrial implants on the bowel itself.⁵

Addressing bladder issues: I routinely administer the PUF (Pain, Urgency, Frequency) questionnaire as part of my intake package and follow it up with conversation. For just about every patient with painful bladder syndrome, pelvic floor physical therapy in combination with a low-acid, low-potassium diet will work effectively together to reduce symptoms and pain. The IC Network offers a helpful food list, and patients can be counseled to choose foods that are also anti-inflammatory. When referrals to a urologist for bladder instillations are possible, these can be helpful as well.

Our communication with patients

Our patients need to have their symptoms and pain validated and to understand why we’re recommending these measures before surgery. Some education is necessary. Few patients will go to an integrative nutritionist, for example, if we just write a referral without explaining how years of inflammation and disruption in the gut can affect the whole body – including mental health – and that it can be corrected over time.

Also necessary is an appreciation of the fact that patients with delayed diagnoses have lived with gastrointestinal and other symptoms and patterns for so long – and often have mothers whose endometriosis caused similar symptoms – that some of their own experiences can seem almost “normal.” A patient whose mother had bowel movements every 7 days may think that 4-5 day intervals are acceptable, for instance. This means we have to carefully consider how we ask our questions.

I always ask my patients as we’re going into surgery, what percentage better are you? I’ve long aimed for at least 30% improvement, but most of the time, with pelvic floor therapy and as many other pain-generator–focused measures as possible, we’re getting them 70% better.

Excision surgery will remove the inflammation that has helped fuel the SIBO and other coconditions. Then, everything done to prepare the body must continue for some time. Certain practices, such as eating an anti-inflammatory diet, should be lifelong.

One day, it is hoped, a pediatrician or other physician will suspect endometriosis early on. The patient will see the surgeon within several months of the onset of pain, and we won’t need to unravel layers of pain generation and CNS upregulation before operating. But until this happens and we shorten the diagnostic delay, we must consider the benefits of presurgical preparation.
 

References

1. Orbuch I, Stein A. Beating Endo: How to Reclaim Your Life From Endometriosis. (New York: HarperCollins, 2019).

2. Healey M et al. J Minim Invasive Gynecol. 2014;21(6):999-1004.

3. Pundir J et al. J Minim Invasive Gynecol. 2017;24(5):747-56.

4. Stratton P, Berkley KJ. Hum Repro Update. 2011;17(3):327-46.

5. Maroun P et al. Aust N Z J Obstet Gynaecol. 2009;49(4):411-4.

Dr. Orbuch is a minimally invasive gynecologic surgeon in Los Angeles who specializes in endometriosis. She has no conflicts of interest to report.

Introduction: The preoperative evaluation for endometriosis – more than meets the eye

It is well known that it often takes 6-10 years for endometriosis to be diagnosed in patients who have the disease, depending on where the patient lives. I certainly am not surprised. During my residency at Parkland Memorial Hospital, if a patient had chronic pelvic pain and no fibroids, her diagnosis was usually pelvic inflammatory disease. Later, during my fellowship in reproductive endocrinology at the University of Pennsylvania, the diagnosis became endometriosis.

As I gained more interest and expertise in the treatment of endometriosis, I became aware of several articles concluding that if a woman sought treatment for chronic pelvic pain with an internist, the diagnosis would be irritable bowel syndrome (IBS); with a urologist, it would be interstitial cystitis; and with a gynecologist, endometriosis. Moreover, there is an increased propensity for IBS and IC in patients with endometriosis. There also is an increased risk of small intestine bacterial overgrowth (SIBO), as noted by our guest author for this latest installment of the Master Class in Gynecologic Surgery, Iris Orbuch, MD.

Like our guest author, I have also noted increased risk of pelvic floor myalgia. Dr. Orbuch clearly outlines why this occurs. In fact, we can now understand why many patients have multiple pelvic pain–inducing issues compounding their pain secondary to endometriosis and leading to remodeling of the central nervous system. Therefore, it certainly makes sense to follow Dr. Orbuch’s recommendation for a multidisciplinary pre- and postsurgical approach “to downregulate the pain generators.”

Dr. Orbuch is a minimally invasive gynecologic surgeon in Los Angeles who specializes in the treatment of patients diagnosed with endometriosis. Dr. Orbuch serves on the Board of Directors of the Foundation of the American Association of Gynecologic Laparoscopists and has served as the chair of the AAGL’s Special Interest Group on Endometriosis and Reproductive Surgery. She is the coauthor of the book “Beating Endo – How to Reclaim Your Life From Endometriosis” (New York: HarperCollins; 2019). The book is written for patients but addresses many issues discussed in this installment of the Master Class in Gynecologic Surgery.

Dr. Miller, MD, FACOG, is professor of obstetrics and gynecology, department of clinical sciences, Rosalind Franklin University of Medicine and Science, North Chicago. He has no conflicts of interest to report.

For optimal surgical outcomes, and to help our patients recover from years of this inflammatory, systemic disease, we must treat our patients holistically and work to downregulate their pain as much as possible before excision surgery. I work with patients a few months prior to surgery, often for 4-5 months, during which time they not only see me for informative follow-ups, but also pelvic floor physical therapists, gastroenterologists, mental health professionals, integrative nutritionists, and physiatrists or pain specialists, depending on their needs.¹

By identifying coexisting conditions in an initial consult and employing a presurgical multidisciplinary approach to downregulate the pain generators, my patients recover well from excision surgery, with greater and faster relief from pain, compared with those using standard approaches, and with little to no use of opioids.

At a minimum, given the unfortunate time constraints and productivity demands of working within health systems – and considering that surgeries are often scheduled a couple of months out – the surgeon could ensure that patients are engaged in at least 6-8 weeks of pelvic floor physical therapy before surgery to sufficiently lengthen the pelvic muscles and loosen surrounding fascia.

Short, tight pelvic floor muscles are almost universal in patients with delayed diagnosis of endometriosis and are significant generators of pain.
 

Appreciating sequelae of diagnostic delay

After my fellowship in advanced laparoscopic and pelvic surgery with Harry Reich, MD, and C. Y. Liu, MD, pioneers of endometriosis excision surgery, and as I did my residency in the early 2000s, I noticed puzzlement in the literature about why some patients still had lasting pain after thorough excision.

I didn’t doubt the efficacy of excision. It is the cornerstone of treatment, and at least one randomized double-blind trial² and a systematic review and meta-analysis³ have demonstrated its superior efficacy over ablation in symptom reduction. What I did doubt was any presumption that surgery alone was enough. I knew there was more to healing when a disease process wreaks havoc on the body for more than a decade and that there were other generators of pain in addition to the endometriosis implants themselves.

As I began to focus on endometriosis in my own surgical practice, I strove to detect and treat endometriosis in teens. But in those patients with longstanding disease, I recognized patterns and began to more fully appreciate the systemic sequelae of endometriosis.

To cope with dysmenorrhea, patients curl up and assume a fetal position, tensing the abdominal muscles, inner thigh muscles, and pelvic floor muscles. Over time, these muscles come to maintain a short, tight, and painful state. (Hence the need for physical therapy to undo this decade-long pattern.)

Endometriosis implants on or near the gastrointestinal tract tug on fascia and muscles and commonly cause constipation, leading women to further overwork the pelvic floor muscles. In the case of diarrhea-predominant dysfunction, our patients squeeze pelvic floor muscles to prevent leakage. And in the case of urinary urgency, they squeeze muscles to release urine that isn’t really there.

As the chronic inflammation of the disease grows, and as pain worsens, the patient is increasingly in sympathetic overdrive (also known as ”fight or flight”), as opposed to a parasympathetic state (also known as “rest and digest”). The bowel’s motility slows, allowing the bacteria of the small intestine to grow beyond what is normal, leading to SIBO, a condition increasingly recognized by gastroenterologists and others that can impede nutrient absorption and cause bloat and pain and exacerbate constipation and diarrhea.

Key to my conceptualization of pain was a review published in 2011 by Pam Stratton, MD, of the National Institutes of Health, and Karen J. Berkley, PhD, then of Florida State University, on chronic pain and endometriosis.⁴ They detailed how endometriotic lesions can develop their own nerve supply that interacts directly and in a two-way fashion with the CNS – and how the lesions can engage the nervous system in ways that create comorbid conditions and pain that becomes “independent of the disease itself.”

Sensitized peripheral nerve fibers innervating a deeply infiltrating lesion on the left uterosacral ligament, for instance, can sensitize neurons in the spinal sacral segment. Branches of these nerve fibers can extend to other segments of the spinal cord, and, once sensitized themselves, turn on neurons in these other segments. There is a resultant remodeling of the central nervous system, in essence, and what is called “remote central sensitization.” The CNS becomes independent from peripheral neural processes.

I now explain to both patients and physicians that those who have had endometriosis for years have had an enduring “hand on the stove,” with a persistent signal to the CNS. Tight muscles are a hand on the stove, painful bladder syndrome is another hand on the stove, and SIBO is yet another. So are anxiety and depression.

The CNS becomes so upregulated and overloaded that messages branch out through the spinal cord to other available pathways and to other organs, muscles, and nerves. The CNS also starts firing on its own – and once it becomes its own pain generator, taking one hand off the stove (for instance, excising implants) while leaving multiple other hands on the hot stove won’t remove all pain. We must downregulate the CNS more broadly.

As I began addressing pain generators and instigators of CNS sensitization – and waiting for excision surgery until the CNS had sufficiently cooled – I saw that my patients had a better chance of more significant and lasting pain relief.
 

Pearls for a multimodal approach

My initial physical exam includes an assessment of the pelvic floor for overly tight musculature. An abdominal exam will usually reveal whether there is asymmetry of the abdominal wall muscles, which typically informs me of the likelihood of tightness and pulling on either side of the pelvic anatomy. On the internal exam, then, the pelvic floor muscles can be palpated and assessed. These findings will guide my referrals and my discussions with patients about the value of pelvic floor physical therapy. The cervix should be in the midline of the vagina – equidistant from the left and right vaginal fornices. If the cervix is pulled away from this midline, and a palpation of a thickened uterosacral ligament reproduces pain, endometriosis is 90% likely.

Patients who report significant “burning” pain that’s suggestive of neuropathic pain should be referred to a physical medicine rehabilitation physician or a pain specialist who can help downregulate their CNS. And patients who have symptoms of depression, anxiety disorders (including obsessive-compulsive disorder), or posttraumatic stress disorder should be referred to pain therapists, psychologists, or other mental health professionals, preferably well before surgery. I will also often discuss mindfulness practices and give my patients “meditation challenges” to achieve during the presurgical phase.

Additional points of emphasis about a multidisciplinary, multimodal approach include:

Advanced pelvic floor therapy: Therapists with specialized training in pelvic health and manual therapy utilize a range of techniques and modalities to release tension in affected muscles, fascia, nerves, and bone, and in doing so, they help to downregulate the CNS. Myofascial release, myofascial trigger point release, neural mobilization, and visceral mobilization are among these techniques. In addition to using manual therapy, many of these therapists may also employ neuromuscular reeducation and other techniques that will be helpful for the longer term.

It is important to identify physical therapists who have training in this approach; women with endometriosis often have a history of treatment by physical therapists whose focus is on incontinence and muscle strengthening (that is, Kegel exercises), which is the opposite of what endometriosis patients need.

Treating SIBO: Symptoms commonly associated with SIBO often overlap with symptoms of irritable bowel syndrome (IBS) – namely constipation, diarrhea (or both), and bloating. Indeed, many patients with undiagnosed endometriosis have been diagnosed with IBS. I send every patient who has one of these symptoms for SIBO breath testing, which utilizes carbohydrate substrates (glucose or lactulose) and measures hydrogen and/or methane in the breath.

SIBO is typically treated with rifampin, which stays in the small bowel and will not negatively affect beneficial bacteria, with or without neomycin. Gastroenterologists with more integrative practices also consider the use of herbals in addition to – or instead of – antibiotics. It can sometimes take months or a couple of years to correct SIBO, depending on how long the patient has been affected, but with presurgical diagnosis and a start on treatment, we can remove or at least tone down another instigator of CNS sensitization.

I estimate that 80% of my patients have tested positive for SIBO. Notably, in a testament to the systemic nature of endometriosis, a study published in 2009 of 355 women undergoing operative laparoscopy for suspected endometriosis found that 90% had gastrointestinal symptoms, but only 7.6% of the vast majority whose endometriosis was confirmed were found to have endometrial implants on the bowel itself.⁵

Addressing bladder issues: I routinely administer the PUF (Pain, Urgency, Frequency) questionnaire as part of my intake package and follow it up with conversation. For just about every patient with painful bladder syndrome, pelvic floor physical therapy in combination with a low-acid, low-potassium diet will work effectively together to reduce symptoms and pain. The IC Network offers a helpful food list, and patients can be counseled to choose foods that are also anti-inflammatory. When referrals to a urologist for bladder instillations are possible, these can be helpful as well.

Our communication with patients

Our patients need to have their symptoms and pain validated and to understand why we’re recommending these measures before surgery. Some education is necessary. Few patients will go to an integrative nutritionist, for example, if we just write a referral without explaining how years of inflammation and disruption in the gut can affect the whole body – including mental health – and that it can be corrected over time.

Also necessary is an appreciation of the fact that patients with delayed diagnoses have lived with gastrointestinal and other symptoms and patterns for so long – and often have mothers whose endometriosis caused similar symptoms – that some of their own experiences can seem almost “normal.” A patient whose mother had bowel movements every 7 days may think that 4-5 day intervals are acceptable, for instance. This means we have to carefully consider how we ask our questions.

I always ask my patients as we’re going into surgery, what percentage better are you? I’ve long aimed for at least 30% improvement, but most of the time, with pelvic floor therapy and as many other pain-generator–focused measures as possible, we’re getting them 70% better.

Excision surgery will remove the inflammation that has helped fuel the SIBO and other coconditions. Then, everything done to prepare the body must continue for some time. Certain practices, such as eating an anti-inflammatory diet, should be lifelong.

One day, it is hoped, a pediatrician or other physician will suspect endometriosis early on. The patient will see the surgeon within several months of the onset of pain, and we won’t need to unravel layers of pain generation and CNS upregulation before operating. But until this happens and we shorten the diagnostic delay, we must consider the benefits of presurgical preparation.
 

References

1. Orbuch I, Stein A. Beating Endo: How to Reclaim Your Life From Endometriosis. (New York: HarperCollins, 2019).

2. Healey M et al. J Minim Invasive Gynecol. 2014;21(6):999-1004.

3. Pundir J et al. J Minim Invasive Gynecol. 2017;24(5):747-56.

4. Stratton P, Berkley KJ. Hum Repro Update. 2011;17(3):327-46.

5. Maroun P et al. Aust N Z J Obstet Gynaecol. 2009;49(4):411-4.

Dr. Orbuch is a minimally invasive gynecologic surgeon in Los Angeles who specializes in endometriosis. She has no conflicts of interest to report.

A multipart study reports that erythritol – a sugar alcohol (polyol) increasingly used as an artificial sweetener that is also made in the body – is associated with risk of major adverse cardiovascular events (MACE) and promotes clotting (thrombosis).

Erythritol is one of the most widely used artificial sweeteners with rapidly increasing prevalence in processed and “keto-related” foods. Artificial sweeteners are “generally recognized as safe” (GRAS) by the U.S. Food and Drug Administration, so there is no requirement for long-term safety studies, and little is known about the long-term health effects.

The current research, published online in Nature Medicine by Marco Witkowski, MD, of the Lerner Research Institute at Cleveland Clinic and colleagues, had multiple parts.

First, in a group of patients undergoing cardiac risk assessment, the researchers found that high levels of polyols, especially erythritol, were associated with increased 3-year risk of MACE, defined as cardiovascular death or nonfatal myocardial infarction or stroke. 

Next, the association of erythritol with this outcome was reproduced in two large U.S. and European groups of stable patients undergoing elective cardiac evaluation.

Next, adding erythritol to whole blood or platelets led to clot activation. And lastly, in eight healthy volunteers, ingesting 30 g of an erythritol-sweetened drink – comparable to a single can of commercially available beverage or a pint of keto ice cream – induced marked and sustained (> 2 day) increases in levels of plasma erythritol.

“Our study shows that when participants consumed an artificially sweetened beverage with an amount of erythritol found in many processed foods, markedly elevated levels in the blood are observed for days – levels well above those observed to enhance clotting risks,” said senior author Stanley L. Hazen, MD, PhD.  

“It is important that further safety studies are conducted to examine the long-term effects of artificial sweeteners in general, and erythritol specifically, on risks for heart attack and stroke, particularly in people at higher risk for cardiovascular disease,” Dr. Hazen, co–section head of preventive cardiology at Cleveland Clinic, said in a press release from his institution.

“Sweeteners like erythritol have rapidly increased in popularity in recent years, but there needs to be more in-depth research into their long-term effects. Cardiovascular disease builds over time, and heart disease is the leading cause of death globally. We need to make sure the foods we eat aren’t hidden contributors,” Dr. Hazen urged.

The topic remains controversial.

Duane Mellor, PhD, a registered dietitian and senior teaching fellow at Aston University, Birmingham, England, told the U.K. Science Media Centre: “This paper effectively shows multiple pieces of a jigsaw exploring the effects of erythritol – although it claims to show an associated risk with the use of erythritol as an artificial sweetener and cardiovascular disease, I believe it fails to do so, as ultimately, erythritol can be made inside our bodies and the intake in most people’s diet is much lower than the amount given in this study.” 

Dr. Hazen countered that data from the 2013-2014 National Health and Nutrition Examination Survey (NHANES) in the United States show that, in some individuals, daily intake of erythritol is estimated to reach 30 g/day. 

“Many try and reduce sugar intake by taking many teaspoons of erythritol in their tea, coffee, etc., instead of sugar,” Dr. Hazen added. “Or they eat keto processed foods that have significant quantities of erythritol within it.”

“These studies are a warning for how our processed food (keto and zero sugar, especially) may inadvertently be causing risk/harm. … in the very subset of subjects who are most vulnerable,” according to Dr. Hazen.
 

Erythritol marketed as ‘zero calorie’, ‘non-nutritive’, or ‘natural’

Patients with type 2 diabetes and obesity are often advised to replace sugar with artificial sweeteners for better glucose control and weight loss, but growing epidemiologic evidence links artificial sweetener consumption with weight gain, insulin resistance, type 2 diabetes, and cardiovascular disease, the researchers write.

Erythritol is naturally present in low amounts in fruits and vegetables; the artificial sweetener erythritol that is produced from corn is only 70% as sweet as sugar.

Upon ingestion it is poorly metabolized, and most is excreted in the urine, so it is characterized as a “zero-calorie,” “non-nutritive,” or “natural sweetener.” It is predicted to double in marketshare in the sweetener sector in the next 5 years.
 

Multipart study

In the first part of their study, in a discovery cohort in 1,157 patients undergoing cardiovascular assessment with 3-year outcomes, the researchers identified polyols that were associated with MACE, and erythritol was among the top MACE-associated molecules.

Next, in a U.S. validation cohort of 2,149 patients, over a 3-year follow-up, patients with plasma levels of erythritol in the highest quartile had a 1.8-fold higher risk of MACE than patients in the lowest quartile (P = .007), after adjusting for cardiovascular risk factors.

In a European validation cohort of 833 patients, over a 3-year follow-up, patients with plasma levels of erythritol in the highest quartile had a 2.21-fold higher risk of MACE than patients in the lowest quartile (P = .010, after adjustment).

At physiologic levels, erythritol enhanced platelet reactivity in vitro and thrombosis formation in vivo.

Finally, in a prospective pilot intervention study, erythritol ingestion in healthy volunteers induced marked and sustained increases in plasma erythritol levels well above thresholds associated with heightened platelet reactivity and thrombosis potential in in vitro and in vivo studies.
 

Others weigh in

“While I think the finding certainly warrants further investigation, don’t throw out your sweeteners just yet,” commented Oliver Jones, PhD, professor of chemistry at the Royal Melbourne Institute of Technology.

“This study only looks at erythritol, and artificial sweeteners are generally considered safe. Any possible (and, as yet unproven) risks of excess erythritol would also need to be balanced against the very real health risks of excess glucose consumption,” he said.

Dr. Hazen responded: “True enough. Erythritol is but one of many artificial sweeteners. That is why it is important to read labels. This study can make patients be informed about how to potentially avoid something that might cause them inadvertent harm.”

“The key findings of this study are that high blood levels of erythritol are strongly associated with cardiovascular outcomes in high-risk patients, which has been replicated in separate validation studies,” said Tom Sanders, DSc, PhD, professor emeritus of nutrition and dietetics, King’s College London.

“Diabetes UK currently advises diabetes patients not to use polyols,” he added.

Dr. Hazen noted that “About three-quarters of the participants had coronary disease, high blood pressure, and about a fifth had diabetes.”

The researchers acknowledge, however, that the observational studies cannot show cause and effect.

The study was supported by the Office of Dietary Supplements at the National Institutes of Health, the Leducq Foundation, and the German Research Foundation (Deutsche Forschungsgemeinschaft). Dr. Mellor, Dr. Jones, and Dr. Sanders have reported no relevant financial relationships.

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

A multipart study reports that erythritol – a sugar alcohol (polyol) increasingly used as an artificial sweetener that is also made in the body – is associated with risk of major adverse cardiovascular events (MACE) and promotes clotting (thrombosis).

Erythritol is one of the most widely used artificial sweeteners with rapidly increasing prevalence in processed and “keto-related” foods. Artificial sweeteners are “generally recognized as safe” (GRAS) by the U.S. Food and Drug Administration, so there is no requirement for long-term safety studies, and little is known about the long-term health effects.

The current research, published online in Nature Medicine by Marco Witkowski, MD, of the Lerner Research Institute at Cleveland Clinic and colleagues, had multiple parts.

First, in a group of patients undergoing cardiac risk assessment, the researchers found that high levels of polyols, especially erythritol, were associated with increased 3-year risk of MACE, defined as cardiovascular death or nonfatal myocardial infarction or stroke. 

Next, the association of erythritol with this outcome was reproduced in two large U.S. and European groups of stable patients undergoing elective cardiac evaluation.

Next, adding erythritol to whole blood or platelets led to clot activation. And lastly, in eight healthy volunteers, ingesting 30 g of an erythritol-sweetened drink – comparable to a single can of commercially available beverage or a pint of keto ice cream – induced marked and sustained (> 2 day) increases in levels of plasma erythritol.

“Our study shows that when participants consumed an artificially sweetened beverage with an amount of erythritol found in many processed foods, markedly elevated levels in the blood are observed for days – levels well above those observed to enhance clotting risks,” said senior author Stanley L. Hazen, MD, PhD.  

“It is important that further safety studies are conducted to examine the long-term effects of artificial sweeteners in general, and erythritol specifically, on risks for heart attack and stroke, particularly in people at higher risk for cardiovascular disease,” Dr. Hazen, co–section head of preventive cardiology at Cleveland Clinic, said in a press release from his institution.

“Sweeteners like erythritol have rapidly increased in popularity in recent years, but there needs to be more in-depth research into their long-term effects. Cardiovascular disease builds over time, and heart disease is the leading cause of death globally. We need to make sure the foods we eat aren’t hidden contributors,” Dr. Hazen urged.

The topic remains controversial.

Duane Mellor, PhD, a registered dietitian and senior teaching fellow at Aston University, Birmingham, England, told the U.K. Science Media Centre: “This paper effectively shows multiple pieces of a jigsaw exploring the effects of erythritol – although it claims to show an associated risk with the use of erythritol as an artificial sweetener and cardiovascular disease, I believe it fails to do so, as ultimately, erythritol can be made inside our bodies and the intake in most people’s diet is much lower than the amount given in this study.” 

Dr. Hazen countered that data from the 2013-2014 National Health and Nutrition Examination Survey (NHANES) in the United States show that, in some individuals, daily intake of erythritol is estimated to reach 30 g/day. 

“Many try and reduce sugar intake by taking many teaspoons of erythritol in their tea, coffee, etc., instead of sugar,” Dr. Hazen added. “Or they eat keto processed foods that have significant quantities of erythritol within it.”

“These studies are a warning for how our processed food (keto and zero sugar, especially) may inadvertently be causing risk/harm. … in the very subset of subjects who are most vulnerable,” according to Dr. Hazen.
 

Erythritol marketed as ‘zero calorie’, ‘non-nutritive’, or ‘natural’

Patients with type 2 diabetes and obesity are often advised to replace sugar with artificial sweeteners for better glucose control and weight loss, but growing epidemiologic evidence links artificial sweetener consumption with weight gain, insulin resistance, type 2 diabetes, and cardiovascular disease, the researchers write.

Erythritol is naturally present in low amounts in fruits and vegetables; the artificial sweetener erythritol that is produced from corn is only 70% as sweet as sugar.

Upon ingestion it is poorly metabolized, and most is excreted in the urine, so it is characterized as a “zero-calorie,” “non-nutritive,” or “natural sweetener.” It is predicted to double in marketshare in the sweetener sector in the next 5 years.
 

Multipart study

In the first part of their study, in a discovery cohort in 1,157 patients undergoing cardiovascular assessment with 3-year outcomes, the researchers identified polyols that were associated with MACE, and erythritol was among the top MACE-associated molecules.

Next, in a U.S. validation cohort of 2,149 patients, over a 3-year follow-up, patients with plasma levels of erythritol in the highest quartile had a 1.8-fold higher risk of MACE than patients in the lowest quartile (P = .007), after adjusting for cardiovascular risk factors.

In a European validation cohort of 833 patients, over a 3-year follow-up, patients with plasma levels of erythritol in the highest quartile had a 2.21-fold higher risk of MACE than patients in the lowest quartile (P = .010, after adjustment).

At physiologic levels, erythritol enhanced platelet reactivity in vitro and thrombosis formation in vivo.

Finally, in a prospective pilot intervention study, erythritol ingestion in healthy volunteers induced marked and sustained increases in plasma erythritol levels well above thresholds associated with heightened platelet reactivity and thrombosis potential in in vitro and in vivo studies.
 

Others weigh in

“While I think the finding certainly warrants further investigation, don’t throw out your sweeteners just yet,” commented Oliver Jones, PhD, professor of chemistry at the Royal Melbourne Institute of Technology.

“This study only looks at erythritol, and artificial sweeteners are generally considered safe. Any possible (and, as yet unproven) risks of excess erythritol would also need to be balanced against the very real health risks of excess glucose consumption,” he said.

Dr. Hazen responded: “True enough. Erythritol is but one of many artificial sweeteners. That is why it is important to read labels. This study can make patients be informed about how to potentially avoid something that might cause them inadvertent harm.”

“The key findings of this study are that high blood levels of erythritol are strongly associated with cardiovascular outcomes in high-risk patients, which has been replicated in separate validation studies,” said Tom Sanders, DSc, PhD, professor emeritus of nutrition and dietetics, King’s College London.

“Diabetes UK currently advises diabetes patients not to use polyols,” he added.

Dr. Hazen noted that “About three-quarters of the participants had coronary disease, high blood pressure, and about a fifth had diabetes.”

The researchers acknowledge, however, that the observational studies cannot show cause and effect.

The study was supported by the Office of Dietary Supplements at the National Institutes of Health, the Leducq Foundation, and the German Research Foundation (Deutsche Forschungsgemeinschaft). Dr. Mellor, Dr. Jones, and Dr. Sanders have reported no relevant financial relationships.

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

A multipart study reports that erythritol – a sugar alcohol (polyol) increasingly used as an artificial sweetener that is also made in the body – is associated with risk of major adverse cardiovascular events (MACE) and promotes clotting (thrombosis).

Erythritol is one of the most widely used artificial sweeteners with rapidly increasing prevalence in processed and “keto-related” foods. Artificial sweeteners are “generally recognized as safe” (GRAS) by the U.S. Food and Drug Administration, so there is no requirement for long-term safety studies, and little is known about the long-term health effects.

The current research, published online in Nature Medicine by Marco Witkowski, MD, of the Lerner Research Institute at Cleveland Clinic and colleagues, had multiple parts.

First, in a group of patients undergoing cardiac risk assessment, the researchers found that high levels of polyols, especially erythritol, were associated with increased 3-year risk of MACE, defined as cardiovascular death or nonfatal myocardial infarction or stroke. 

Next, the association of erythritol with this outcome was reproduced in two large U.S. and European groups of stable patients undergoing elective cardiac evaluation.

Next, adding erythritol to whole blood or platelets led to clot activation. And lastly, in eight healthy volunteers, ingesting 30 g of an erythritol-sweetened drink – comparable to a single can of commercially available beverage or a pint of keto ice cream – induced marked and sustained (> 2 day) increases in levels of plasma erythritol.

“Our study shows that when participants consumed an artificially sweetened beverage with an amount of erythritol found in many processed foods, markedly elevated levels in the blood are observed for days – levels well above those observed to enhance clotting risks,” said senior author Stanley L. Hazen, MD, PhD.  

“It is important that further safety studies are conducted to examine the long-term effects of artificial sweeteners in general, and erythritol specifically, on risks for heart attack and stroke, particularly in people at higher risk for cardiovascular disease,” Dr. Hazen, co–section head of preventive cardiology at Cleveland Clinic, said in a press release from his institution.

“Sweeteners like erythritol have rapidly increased in popularity in recent years, but there needs to be more in-depth research into their long-term effects. Cardiovascular disease builds over time, and heart disease is the leading cause of death globally. We need to make sure the foods we eat aren’t hidden contributors,” Dr. Hazen urged.

The topic remains controversial.

Duane Mellor, PhD, a registered dietitian and senior teaching fellow at Aston University, Birmingham, England, told the U.K. Science Media Centre: “This paper effectively shows multiple pieces of a jigsaw exploring the effects of erythritol – although it claims to show an associated risk with the use of erythritol as an artificial sweetener and cardiovascular disease, I believe it fails to do so, as ultimately, erythritol can be made inside our bodies and the intake in most people’s diet is much lower than the amount given in this study.” 

Dr. Hazen countered that data from the 2013-2014 National Health and Nutrition Examination Survey (NHANES) in the United States show that, in some individuals, daily intake of erythritol is estimated to reach 30 g/day. 

“Many try and reduce sugar intake by taking many teaspoons of erythritol in their tea, coffee, etc., instead of sugar,” Dr. Hazen added. “Or they eat keto processed foods that have significant quantities of erythritol within it.”

“These studies are a warning for how our processed food (keto and zero sugar, especially) may inadvertently be causing risk/harm. … in the very subset of subjects who are most vulnerable,” according to Dr. Hazen.
 

Erythritol marketed as ‘zero calorie’, ‘non-nutritive’, or ‘natural’

Patients with type 2 diabetes and obesity are often advised to replace sugar with artificial sweeteners for better glucose control and weight loss, but growing epidemiologic evidence links artificial sweetener consumption with weight gain, insulin resistance, type 2 diabetes, and cardiovascular disease, the researchers write.

Erythritol is naturally present in low amounts in fruits and vegetables; the artificial sweetener erythritol that is produced from corn is only 70% as sweet as sugar.

Upon ingestion it is poorly metabolized, and most is excreted in the urine, so it is characterized as a “zero-calorie,” “non-nutritive,” or “natural sweetener.” It is predicted to double in marketshare in the sweetener sector in the next 5 years.
 

Multipart study

In the first part of their study, in a discovery cohort in 1,157 patients undergoing cardiovascular assessment with 3-year outcomes, the researchers identified polyols that were associated with MACE, and erythritol was among the top MACE-associated molecules.

Next, in a U.S. validation cohort of 2,149 patients, over a 3-year follow-up, patients with plasma levels of erythritol in the highest quartile had a 1.8-fold higher risk of MACE than patients in the lowest quartile (P = .007), after adjusting for cardiovascular risk factors.

In a European validation cohort of 833 patients, over a 3-year follow-up, patients with plasma levels of erythritol in the highest quartile had a 2.21-fold higher risk of MACE than patients in the lowest quartile (P = .010, after adjustment).

At physiologic levels, erythritol enhanced platelet reactivity in vitro and thrombosis formation in vivo.

Finally, in a prospective pilot intervention study, erythritol ingestion in healthy volunteers induced marked and sustained increases in plasma erythritol levels well above thresholds associated with heightened platelet reactivity and thrombosis potential in in vitro and in vivo studies.
 

Others weigh in

“While I think the finding certainly warrants further investigation, don’t throw out your sweeteners just yet,” commented Oliver Jones, PhD, professor of chemistry at the Royal Melbourne Institute of Technology.

“This study only looks at erythritol, and artificial sweeteners are generally considered safe. Any possible (and, as yet unproven) risks of excess erythritol would also need to be balanced against the very real health risks of excess glucose consumption,” he said.

Dr. Hazen responded: “True enough. Erythritol is but one of many artificial sweeteners. That is why it is important to read labels. This study can make patients be informed about how to potentially avoid something that might cause them inadvertent harm.”

“The key findings of this study are that high blood levels of erythritol are strongly associated with cardiovascular outcomes in high-risk patients, which has been replicated in separate validation studies,” said Tom Sanders, DSc, PhD, professor emeritus of nutrition and dietetics, King’s College London.

“Diabetes UK currently advises diabetes patients not to use polyols,” he added.

Dr. Hazen noted that “About three-quarters of the participants had coronary disease, high blood pressure, and about a fifth had diabetes.”

The researchers acknowledge, however, that the observational studies cannot show cause and effect.

The study was supported by the Office of Dietary Supplements at the National Institutes of Health, the Leducq Foundation, and the German Research Foundation (Deutsche Forschungsgemeinschaft). Dr. Mellor, Dr. Jones, and Dr. Sanders have reported no relevant financial relationships.

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

SAN DIEGO – Diagnosis of multiple sclerosis (MS) presents a number of challenges, and differential diagnosis is critical to get patients on therapy earlier in the disease process.

The problem is that MS can vary greatly in its presentation, and many symptoms can mimic other conditions, according to Eoin Flanagan, MBBCh, who discussed the issue during a session at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
 

Mimics and red flags

Dr. Flanagan noted a study that found common themes among MS misdiagnoses. “Many of these conditions are common conditions that we see in our neurology clinic – for example, migraine, fibromyalgia, nonspecific symptoms with an abnormal MRI, or functional neurologic disorder. If you’re teaching medical students or trainees about MS misdiagnosis, it’s important to give this example to show that these are not the zebras that are misdiagnosed, but actually common conditions that we see in our clinics,” said Dr. Flanagan, a neurologist at Mayo Clinic in Rochester, Minn.

Evaluation of MS mimics isn’t always necessary. Much of the time, typical clinical, neurologic, and imaging features provide a clear diagnosis. But some features can be red flags that MS may not be the cause. These can include a cerebrospinal fluid white blood cell count higher than 50, elevated CSF protein with normal white cell counts, low glucose, and negative oligoclonal bands, all of which could signify a range of other conditions.

These and other red flags should prompt a careful look to get the right diagnosis.
 

Earlier diagnosis = better outcomes

“[Evidence has] shown recently that as the diagnostic criteria have become more sensitive and we diagnose MS earlier, patients have had better outcomes because they’ve been able to initiate treatment earlier,” said Andrew Solomon, MD, who is an associate professor of neurologic sciences and division chief of multiple sclerosis at University of Vermont, Burlington. Dr. Solomon, Dr. Flanagan, and others are currently writing a review article on differential diagnosis of MS that will update the last review, published in 2008.

“Differential diagnosis has become more complex as we’ve had a broader understanding of disorders that can mimic MS. In the meantime, we still don’t have a highly sensitive and specific biomarker for MS that can help guide us when we first see somebody,” said Dr. Solomon.
 

Look for patterns and imaging clues

Dr. Flanagan’s talk had several points of emphasis. A key feature is the length of time between when the patient develops the first symptom and maximal symptoms. “If that’s very quick, then that suggests it’s a spinal cord stroke. If it comes down over days to a few weeks, then that suggests inflammation like MS, or like neuromyelitis optica [NMO] or myelin oligodendrocyte glycoprotein antibody-associated disease [MOGAD]. As it progresses beyond 21 days, then we’re going to be thinking about a different diagnosis,” said Dr. Flanagan.

Dr. Flanagan also noted the usefulness of specific features of the spinal cord MRI. Variables like lesion length, location in the center or periphery of the spinal cord, and characteristics of the enhancement pattern may be useful. “The pattern of gadolinium enhancement can be useful in narrowing your differential diagnosis and suggesting the correct diagnosis. For example, the flat pancake-like enhancement on sagittal images can suggest cervical spondylosis, while trident sign on axial images can suggest spinal cord sarcoidosis. Prior studies have shown that education on these patterns can enhance diagnosis.”

Dr. Flanagan suggested that both radiologists and neurologists should be trained to recognize such patterns. “If you educate radiologists or neurologists on these patterns, it can help them with diagnosis.”
 

Common mistakes

MOGAD and aquaporin 4–positive NMO spectrum disorder (AQP4+NMOSD) can be easily mistaken for MS, but there are some key differences. MOGAD and AQP4+NMOSD attacks are more severe than MS attacks, leaving patients more likely to be blind following an optic neuritis attack or wheelchair bound because of myelitis. More than 85% of CSF from patients with MS have oligoclonal bands versus about 15% of CSF from patients with MOGAD or AQP4+NMOSD. There is also a difference in lesion dynamics over time: MOGAD T2 lesions frequently resolve over follow-up while AQP4+NMOSD and MS lesions typically continue and leave a scar and persist. Silent lesions are more likely during surveillance MRI among MS patients, but are rare in MOGAD and AQP4+NMOSD, according to Dr. Flanagan. “One caveat to this is that with stronger MS medications we are seeing less silent lesions accumulating as we use those treatments more often.”

Dr. Solomon has been done nonpromotional speaking for EMD Serono. He has received research funding from Bristol-Myers Squibb. He has been on an advisory board or consulted for Greenwich Biosciences, TG Therapeutics, Octave Bioscience, and Horizon Therapeutics. Dr. Flanagan has no relevant financial disclosures. Dr. Flanagan has served on advisory boards for Alexion, Genentech, Horizon Therapeutics, and UCB.

SAN DIEGO – Diagnosis of multiple sclerosis (MS) presents a number of challenges, and differential diagnosis is critical to get patients on therapy earlier in the disease process.

The problem is that MS can vary greatly in its presentation, and many symptoms can mimic other conditions, according to Eoin Flanagan, MBBCh, who discussed the issue during a session at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
 

Mimics and red flags

Dr. Flanagan noted a study that found common themes among MS misdiagnoses. “Many of these conditions are common conditions that we see in our neurology clinic – for example, migraine, fibromyalgia, nonspecific symptoms with an abnormal MRI, or functional neurologic disorder. If you’re teaching medical students or trainees about MS misdiagnosis, it’s important to give this example to show that these are not the zebras that are misdiagnosed, but actually common conditions that we see in our clinics,” said Dr. Flanagan, a neurologist at Mayo Clinic in Rochester, Minn.

Evaluation of MS mimics isn’t always necessary. Much of the time, typical clinical, neurologic, and imaging features provide a clear diagnosis. But some features can be red flags that MS may not be the cause. These can include a cerebrospinal fluid white blood cell count higher than 50, elevated CSF protein with normal white cell counts, low glucose, and negative oligoclonal bands, all of which could signify a range of other conditions.

These and other red flags should prompt a careful look to get the right diagnosis.
 

Earlier diagnosis = better outcomes

“[Evidence has] shown recently that as the diagnostic criteria have become more sensitive and we diagnose MS earlier, patients have had better outcomes because they’ve been able to initiate treatment earlier,” said Andrew Solomon, MD, who is an associate professor of neurologic sciences and division chief of multiple sclerosis at University of Vermont, Burlington. Dr. Solomon, Dr. Flanagan, and others are currently writing a review article on differential diagnosis of MS that will update the last review, published in 2008.

“Differential diagnosis has become more complex as we’ve had a broader understanding of disorders that can mimic MS. In the meantime, we still don’t have a highly sensitive and specific biomarker for MS that can help guide us when we first see somebody,” said Dr. Solomon.
 

Look for patterns and imaging clues

Dr. Flanagan’s talk had several points of emphasis. A key feature is the length of time between when the patient develops the first symptom and maximal symptoms. “If that’s very quick, then that suggests it’s a spinal cord stroke. If it comes down over days to a few weeks, then that suggests inflammation like MS, or like neuromyelitis optica [NMO] or myelin oligodendrocyte glycoprotein antibody-associated disease [MOGAD]. As it progresses beyond 21 days, then we’re going to be thinking about a different diagnosis,” said Dr. Flanagan.

Dr. Flanagan also noted the usefulness of specific features of the spinal cord MRI. Variables like lesion length, location in the center or periphery of the spinal cord, and characteristics of the enhancement pattern may be useful. “The pattern of gadolinium enhancement can be useful in narrowing your differential diagnosis and suggesting the correct diagnosis. For example, the flat pancake-like enhancement on sagittal images can suggest cervical spondylosis, while trident sign on axial images can suggest spinal cord sarcoidosis. Prior studies have shown that education on these patterns can enhance diagnosis.”

Dr. Flanagan suggested that both radiologists and neurologists should be trained to recognize such patterns. “If you educate radiologists or neurologists on these patterns, it can help them with diagnosis.”
 

Common mistakes

MOGAD and aquaporin 4–positive NMO spectrum disorder (AQP4+NMOSD) can be easily mistaken for MS, but there are some key differences. MOGAD and AQP4+NMOSD attacks are more severe than MS attacks, leaving patients more likely to be blind following an optic neuritis attack or wheelchair bound because of myelitis. More than 85% of CSF from patients with MS have oligoclonal bands versus about 15% of CSF from patients with MOGAD or AQP4+NMOSD. There is also a difference in lesion dynamics over time: MOGAD T2 lesions frequently resolve over follow-up while AQP4+NMOSD and MS lesions typically continue and leave a scar and persist. Silent lesions are more likely during surveillance MRI among MS patients, but are rare in MOGAD and AQP4+NMOSD, according to Dr. Flanagan. “One caveat to this is that with stronger MS medications we are seeing less silent lesions accumulating as we use those treatments more often.”

Dr. Solomon has been done nonpromotional speaking for EMD Serono. He has received research funding from Bristol-Myers Squibb. He has been on an advisory board or consulted for Greenwich Biosciences, TG Therapeutics, Octave Bioscience, and Horizon Therapeutics. Dr. Flanagan has no relevant financial disclosures. Dr. Flanagan has served on advisory boards for Alexion, Genentech, Horizon Therapeutics, and UCB.

SAN DIEGO – Diagnosis of multiple sclerosis (MS) presents a number of challenges, and differential diagnosis is critical to get patients on therapy earlier in the disease process.

The problem is that MS can vary greatly in its presentation, and many symptoms can mimic other conditions, according to Eoin Flanagan, MBBCh, who discussed the issue during a session at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
 

Mimics and red flags

Dr. Flanagan noted a study that found common themes among MS misdiagnoses. “Many of these conditions are common conditions that we see in our neurology clinic – for example, migraine, fibromyalgia, nonspecific symptoms with an abnormal MRI, or functional neurologic disorder. If you’re teaching medical students or trainees about MS misdiagnosis, it’s important to give this example to show that these are not the zebras that are misdiagnosed, but actually common conditions that we see in our clinics,” said Dr. Flanagan, a neurologist at Mayo Clinic in Rochester, Minn.

Evaluation of MS mimics isn’t always necessary. Much of the time, typical clinical, neurologic, and imaging features provide a clear diagnosis. But some features can be red flags that MS may not be the cause. These can include a cerebrospinal fluid white blood cell count higher than 50, elevated CSF protein with normal white cell counts, low glucose, and negative oligoclonal bands, all of which could signify a range of other conditions.

These and other red flags should prompt a careful look to get the right diagnosis.
 

Earlier diagnosis = better outcomes

“[Evidence has] shown recently that as the diagnostic criteria have become more sensitive and we diagnose MS earlier, patients have had better outcomes because they’ve been able to initiate treatment earlier,” said Andrew Solomon, MD, who is an associate professor of neurologic sciences and division chief of multiple sclerosis at University of Vermont, Burlington. Dr. Solomon, Dr. Flanagan, and others are currently writing a review article on differential diagnosis of MS that will update the last review, published in 2008.

“Differential diagnosis has become more complex as we’ve had a broader understanding of disorders that can mimic MS. In the meantime, we still don’t have a highly sensitive and specific biomarker for MS that can help guide us when we first see somebody,” said Dr. Solomon.
 

Look for patterns and imaging clues

Dr. Flanagan’s talk had several points of emphasis. A key feature is the length of time between when the patient develops the first symptom and maximal symptoms. “If that’s very quick, then that suggests it’s a spinal cord stroke. If it comes down over days to a few weeks, then that suggests inflammation like MS, or like neuromyelitis optica [NMO] or myelin oligodendrocyte glycoprotein antibody-associated disease [MOGAD]. As it progresses beyond 21 days, then we’re going to be thinking about a different diagnosis,” said Dr. Flanagan.

Dr. Flanagan also noted the usefulness of specific features of the spinal cord MRI. Variables like lesion length, location in the center or periphery of the spinal cord, and characteristics of the enhancement pattern may be useful. “The pattern of gadolinium enhancement can be useful in narrowing your differential diagnosis and suggesting the correct diagnosis. For example, the flat pancake-like enhancement on sagittal images can suggest cervical spondylosis, while trident sign on axial images can suggest spinal cord sarcoidosis. Prior studies have shown that education on these patterns can enhance diagnosis.”

Dr. Flanagan suggested that both radiologists and neurologists should be trained to recognize such patterns. “If you educate radiologists or neurologists on these patterns, it can help them with diagnosis.”
 

Common mistakes

MOGAD and aquaporin 4–positive NMO spectrum disorder (AQP4+NMOSD) can be easily mistaken for MS, but there are some key differences. MOGAD and AQP4+NMOSD attacks are more severe than MS attacks, leaving patients more likely to be blind following an optic neuritis attack or wheelchair bound because of myelitis. More than 85% of CSF from patients with MS have oligoclonal bands versus about 15% of CSF from patients with MOGAD or AQP4+NMOSD. There is also a difference in lesion dynamics over time: MOGAD T2 lesions frequently resolve over follow-up while AQP4+NMOSD and MS lesions typically continue and leave a scar and persist. Silent lesions are more likely during surveillance MRI among MS patients, but are rare in MOGAD and AQP4+NMOSD, according to Dr. Flanagan. “One caveat to this is that with stronger MS medications we are seeing less silent lesions accumulating as we use those treatments more often.”

Dr. Solomon has been done nonpromotional speaking for EMD Serono. He has received research funding from Bristol-Myers Squibb. He has been on an advisory board or consulted for Greenwich Biosciences, TG Therapeutics, Octave Bioscience, and Horizon Therapeutics. Dr. Flanagan has no relevant financial disclosures. Dr. Flanagan has served on advisory boards for Alexion, Genentech, Horizon Therapeutics, and UCB.

Combining ketamine and psychotherapy is a promising approach for treating PTSD, new research suggests.

In a systematic review and meta-analysis of four studies investigating combined use of psychotherapy and ketamine for PTSD, results showed that all the studies showed a significant reduction in PTSD symptom scores.

Overall, the treatment was “highly effective, as seen by the significant improvements in symptoms on multiple measures,” Aaron E. Philipp-Muller, BScH, Centre for Neuroscience Studies, Queen’s University, Kingston, Ont., and colleagues write.

Furthermore, the study “demonstrates the potential feasibility of this treatment model and corroborates previous work,” the investigators write.

However, a limitation they note was that only 34 participants were included in the analysis.

The findings were published online in the Journal of Clinical Psychiatry.
 

Emerging treatment

Ketamine is an “emerging treatment for a number of psychopathologies, such as major depressive disorder and PTSD, with a higher response than other pharmacologic agents,” the researchers write.

It is hypothesized that ketamine rapidly facilitates long-term potentiation, “thereby allowing a patient to disengage from an established pattern of thought more readily,” they write.

However, ketamine has several drawbacks, including the fact that it brings only 1 week of relief for PTSD. Also, because it must be administered intravenously, it is “impractical for long-term weekly administration,” they note.

Pharmacologically enhanced psychotherapy is a potential way to prolong ketamine’s effects. Several prior studies have investigated this model using other psychedelic medications, with encouraging results.

The current investigators decided to review all literature to date on the subject of ketamine plus psychotherapy for the treatment of PTSD.

To be included, the study had to include patients diagnosed with PTSD, an intervention involving ketamine alongside any form of psychotherapy, and assessment of all patients before and after treatment using the Clinician-Administered PTSD Scale (CAPS) or the PTSD Checklist (PCL).

Four studies met inclusion criteria. Of these, two were of “moderate” quality and two were of “low” quality, based on the GRADE assessment. The studies encompassed a total of 34 patients with “diverse traumatic experiences” and included several types of ketamine administration protocols, including one used previously for treating depression and another used previously for chronic pain.

The psychotherapy modalities also differed between the studies. In two studies, patients received 12 sessions of trauma interventions using mindfulness-based extinction and reconsolidation therapy; in a third study, patients received 10 weekly sessions of prolonged exposure therapy; and in the fourth study, patients received five daily sessions of exposure therapy.

Across the studies, the psychotherapies were paired differently with ketamine administration, such as the number of ketamine administrations in conjunction with therapy.

Despite the differences in protocols, all the studies of ketamine plus psychotherapy showed a significant reduction in PTSD symptoms, with a pooled standardized mean difference (SMD) of –7.26 (95% CI, –12.28 to –2.25; P = .005) for the CAPS and a pooled SMD of –5.17 (95% CI, –7.99 to –2.35; P < .001) for the PCL.

The researchers acknowledge that the sample size was very small “due to the novelty of this research area.” This prompted the inclusion of nonrandomized studies that “lowered the quality of the evidence,” they note.

Nevertheless, “these preliminary findings indicate the potential of ketamine-assisted psychotherapy for PTSD,” the investigators write.
 

A promising avenue?

In a comment, Dan Iosifescu, MD, professor of psychiatry, New York University School of Medicine, called the combination of ketamine and psychotherapy in PTSD “a very promising treatment avenue.”

Dr. Iosifescu, who was not involved with the research, noted that “several PTSD-focused psychotherapies are ultimately very effective but very hard to tolerate for participants.” For example, prolonged exposure therapy has dropout rates as high as 50%.

In addition, ketamine has rapid but not sustained effects in PTSD, he said.

“So in theory, a course of ketamine could help PTSD patients improve rapidly and tolerate the psychotherapy, which could provide sustained benefits,” he added.

However, Dr. Iosifescu cautioned that the data supporting this “is very sparse for now.”

He also noted that the meta-analysis included only “four tiny studies” and had only 34 total participants. In addition, several of the studies had no comparison group and the study designs were all different – “both with respect to the administration of ketamine and to the paired PTSD psychotherapy.”

For this reason, “any conclusions are only a very preliminary suggestion that this may be a fruitful avenue,” he said.

Dr. Iosifescu added that additional studies on this topic are ongoing. The largest one at the Veterans Administration will hopefully include 100 participants and “will provide more reliable evidence for this important topic,” he said.

The study was indirectly supported by the Internal Faculty Grant from the department of psychiatry, Queen’s University. Dr. Iosifescu reported no relevant financial relationships.

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

Combining ketamine and psychotherapy is a promising approach for treating PTSD, new research suggests.

In a systematic review and meta-analysis of four studies investigating combined use of psychotherapy and ketamine for PTSD, results showed that all the studies showed a significant reduction in PTSD symptom scores.

Overall, the treatment was “highly effective, as seen by the significant improvements in symptoms on multiple measures,” Aaron E. Philipp-Muller, BScH, Centre for Neuroscience Studies, Queen’s University, Kingston, Ont., and colleagues write.

Furthermore, the study “demonstrates the potential feasibility of this treatment model and corroborates previous work,” the investigators write.

However, a limitation they note was that only 34 participants were included in the analysis.

The findings were published online in the Journal of Clinical Psychiatry.
 

Emerging treatment

Ketamine is an “emerging treatment for a number of psychopathologies, such as major depressive disorder and PTSD, with a higher response than other pharmacologic agents,” the researchers write.

It is hypothesized that ketamine rapidly facilitates long-term potentiation, “thereby allowing a patient to disengage from an established pattern of thought more readily,” they write.

However, ketamine has several drawbacks, including the fact that it brings only 1 week of relief for PTSD. Also, because it must be administered intravenously, it is “impractical for long-term weekly administration,” they note.

Pharmacologically enhanced psychotherapy is a potential way to prolong ketamine’s effects. Several prior studies have investigated this model using other psychedelic medications, with encouraging results.

The current investigators decided to review all literature to date on the subject of ketamine plus psychotherapy for the treatment of PTSD.

To be included, the study had to include patients diagnosed with PTSD, an intervention involving ketamine alongside any form of psychotherapy, and assessment of all patients before and after treatment using the Clinician-Administered PTSD Scale (CAPS) or the PTSD Checklist (PCL).

Four studies met inclusion criteria. Of these, two were of “moderate” quality and two were of “low” quality, based on the GRADE assessment. The studies encompassed a total of 34 patients with “diverse traumatic experiences” and included several types of ketamine administration protocols, including one used previously for treating depression and another used previously for chronic pain.

The psychotherapy modalities also differed between the studies. In two studies, patients received 12 sessions of trauma interventions using mindfulness-based extinction and reconsolidation therapy; in a third study, patients received 10 weekly sessions of prolonged exposure therapy; and in the fourth study, patients received five daily sessions of exposure therapy.

Across the studies, the psychotherapies were paired differently with ketamine administration, such as the number of ketamine administrations in conjunction with therapy.

Despite the differences in protocols, all the studies of ketamine plus psychotherapy showed a significant reduction in PTSD symptoms, with a pooled standardized mean difference (SMD) of –7.26 (95% CI, –12.28 to –2.25; P = .005) for the CAPS and a pooled SMD of –5.17 (95% CI, –7.99 to –2.35; P < .001) for the PCL.

The researchers acknowledge that the sample size was very small “due to the novelty of this research area.” This prompted the inclusion of nonrandomized studies that “lowered the quality of the evidence,” they note.

Nevertheless, “these preliminary findings indicate the potential of ketamine-assisted psychotherapy for PTSD,” the investigators write.
 

A promising avenue?

In a comment, Dan Iosifescu, MD, professor of psychiatry, New York University School of Medicine, called the combination of ketamine and psychotherapy in PTSD “a very promising treatment avenue.”

Dr. Iosifescu, who was not involved with the research, noted that “several PTSD-focused psychotherapies are ultimately very effective but very hard to tolerate for participants.” For example, prolonged exposure therapy has dropout rates as high as 50%.

In addition, ketamine has rapid but not sustained effects in PTSD, he said.

“So in theory, a course of ketamine could help PTSD patients improve rapidly and tolerate the psychotherapy, which could provide sustained benefits,” he added.

However, Dr. Iosifescu cautioned that the data supporting this “is very sparse for now.”

He also noted that the meta-analysis included only “four tiny studies” and had only 34 total participants. In addition, several of the studies had no comparison group and the study designs were all different – “both with respect to the administration of ketamine and to the paired PTSD psychotherapy.”

For this reason, “any conclusions are only a very preliminary suggestion that this may be a fruitful avenue,” he said.

Dr. Iosifescu added that additional studies on this topic are ongoing. The largest one at the Veterans Administration will hopefully include 100 participants and “will provide more reliable evidence for this important topic,” he said.

The study was indirectly supported by the Internal Faculty Grant from the department of psychiatry, Queen’s University. Dr. Iosifescu reported no relevant financial relationships.

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

Combining ketamine and psychotherapy is a promising approach for treating PTSD, new research suggests.

In a systematic review and meta-analysis of four studies investigating combined use of psychotherapy and ketamine for PTSD, results showed that all the studies showed a significant reduction in PTSD symptom scores.

Overall, the treatment was “highly effective, as seen by the significant improvements in symptoms on multiple measures,” Aaron E. Philipp-Muller, BScH, Centre for Neuroscience Studies, Queen’s University, Kingston, Ont., and colleagues write.

Furthermore, the study “demonstrates the potential feasibility of this treatment model and corroborates previous work,” the investigators write.

However, a limitation they note was that only 34 participants were included in the analysis.

The findings were published online in the Journal of Clinical Psychiatry.
 

Emerging treatment

Ketamine is an “emerging treatment for a number of psychopathologies, such as major depressive disorder and PTSD, with a higher response than other pharmacologic agents,” the researchers write.

It is hypothesized that ketamine rapidly facilitates long-term potentiation, “thereby allowing a patient to disengage from an established pattern of thought more readily,” they write.

However, ketamine has several drawbacks, including the fact that it brings only 1 week of relief for PTSD. Also, because it must be administered intravenously, it is “impractical for long-term weekly administration,” they note.

Pharmacologically enhanced psychotherapy is a potential way to prolong ketamine’s effects. Several prior studies have investigated this model using other psychedelic medications, with encouraging results.

The current investigators decided to review all literature to date on the subject of ketamine plus psychotherapy for the treatment of PTSD.

To be included, the study had to include patients diagnosed with PTSD, an intervention involving ketamine alongside any form of psychotherapy, and assessment of all patients before and after treatment using the Clinician-Administered PTSD Scale (CAPS) or the PTSD Checklist (PCL).

Four studies met inclusion criteria. Of these, two were of “moderate” quality and two were of “low” quality, based on the GRADE assessment. The studies encompassed a total of 34 patients with “diverse traumatic experiences” and included several types of ketamine administration protocols, including one used previously for treating depression and another used previously for chronic pain.

The psychotherapy modalities also differed between the studies. In two studies, patients received 12 sessions of trauma interventions using mindfulness-based extinction and reconsolidation therapy; in a third study, patients received 10 weekly sessions of prolonged exposure therapy; and in the fourth study, patients received five daily sessions of exposure therapy.

Across the studies, the psychotherapies were paired differently with ketamine administration, such as the number of ketamine administrations in conjunction with therapy.

Despite the differences in protocols, all the studies of ketamine plus psychotherapy showed a significant reduction in PTSD symptoms, with a pooled standardized mean difference (SMD) of –7.26 (95% CI, –12.28 to –2.25; P = .005) for the CAPS and a pooled SMD of –5.17 (95% CI, –7.99 to –2.35; P < .001) for the PCL.

The researchers acknowledge that the sample size was very small “due to the novelty of this research area.” This prompted the inclusion of nonrandomized studies that “lowered the quality of the evidence,” they note.

Nevertheless, “these preliminary findings indicate the potential of ketamine-assisted psychotherapy for PTSD,” the investigators write.
 

A promising avenue?

In a comment, Dan Iosifescu, MD, professor of psychiatry, New York University School of Medicine, called the combination of ketamine and psychotherapy in PTSD “a very promising treatment avenue.”

Dr. Iosifescu, who was not involved with the research, noted that “several PTSD-focused psychotherapies are ultimately very effective but very hard to tolerate for participants.” For example, prolonged exposure therapy has dropout rates as high as 50%.

In addition, ketamine has rapid but not sustained effects in PTSD, he said.

“So in theory, a course of ketamine could help PTSD patients improve rapidly and tolerate the psychotherapy, which could provide sustained benefits,” he added.

However, Dr. Iosifescu cautioned that the data supporting this “is very sparse for now.”

He also noted that the meta-analysis included only “four tiny studies” and had only 34 total participants. In addition, several of the studies had no comparison group and the study designs were all different – “both with respect to the administration of ketamine and to the paired PTSD psychotherapy.”

For this reason, “any conclusions are only a very preliminary suggestion that this may be a fruitful avenue,” he said.

Dr. Iosifescu added that additional studies on this topic are ongoing. The largest one at the Veterans Administration will hopefully include 100 participants and “will provide more reliable evidence for this important topic,” he said.

The study was indirectly supported by the Internal Faculty Grant from the department of psychiatry, Queen’s University. Dr. Iosifescu reported no relevant financial relationships.

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

In recent weeks, you may have noticed some familiar headlines about red wine and cardiovascular health. Why the sudden return of these stories? Because of an article recently published in the American Journal of Clinical Nutrition.

Funded in part by a grant from the São Paulo Research Foundation (FAPESP), the “Wine Flora Study” was carried out by prominent researchers from institutions in South America, Europe, and the United States: University of São Paulo; State University of Campinas, São Paulo; University of Brasília; University of Verona (Italy); Austrian Institute of Technology, Tulln; and Harvard Medical School, Boston. The team looked into the effects of red wine on gut flora and plasma levels of trimethylamine-N-oxide (TMAO). And what they found was quite interesting.
 

The study

Previous results have pointed to the beneficial effect that red wine has on the gut microbiome.

The Wine Flora Study involved 42 men (average age, 60 years) with documented coronary artery disease. The trial encompassed two 3-week interventions. In one, the participants consumed 250 mL of red wine per day; the red wine sample had an alcohol content (% v) of 12.75. The Brazilian Wine Institute produced and supplied the red wine: a 2014 Merlot bottled in August 2016 and customized for the study. The second intervention involved alcohol abstention.

Each intervention was preceded by a 2-week washout period. Because certain foods and drinks could interfere with the results, the participants were instructed not to consume alcoholic beverages, fermented foods (yogurt, kombucha, soy lecithin, kefir, sauerkraut, and other fermented vegetables), synthetic prebiotics (insulin, fructooligosaccharides), fiber, dairy, food polyphenols (grapes, grape juice, cranberries, strawberries), and probiotics.

At each intervention, the gut microbiota was analyzed via 16S ribosomal RNA highthroughput sequencing. This method makes it possible to identify bacterial species. The plasma metabolome of 20 randomly selected participants was evaluated by ultra–high-performance liquid chromatography with tandem mass spectrometry. In this method, liquid chromatography separates the compounds, and a mass spectrometer is used to analyze them.

One of the metabolites of interest was TMAO, which is produced from the trimethylamine released when gut bacteria process protein-rich foods. TMAO has been identified as playing a role in the development of atherosclerosis.
 

Results

After red wine consumption, there was significant remodeling of the gut microbiota, with a difference in beta diversity and predominance of Parasutterella, Ruminococcaceae, several Bacteroides species, and Prevotella.

Plasma metabolomic analysis revealed significant changes in metabolites after red wine consumption, consistent with improved redox homeostasis, which is involved in the oxidative stress that promotes atherosclerosis.

Plasma TMAO, however, did not differ between red wine intervention and alcohol abstention.
 

Implications

The researchers concluded that modulation of the gut microbiota may contribute to the putative cardiovascular benefits of moderate red wine consumption. But, as they were careful to point out in the very title of the study, a red wine intervention does not modify plasma TMAO. They also mentioned that the 3-week period may have been too short for the findings to serve as the basis for promoting any meaningful modification. In addition, the team emphasized that these data remain hypothesisgenerating and pave the way for future research.

In an interview with FAPESP, the study’s corresponding author, Protásio Lemos da Luz, MD, PhD, warned about the risks associated with drinking too much alcohol (> 8.5 oz., or 250 mL, of wine daily).

It should be kept in mind that, in Brazil, people do not drink nearly as much wine as they do beer or liquor. Furthermore, the evidence that is available does not provide confirmation of the existence or the extent of the protective health effects associated with light or moderate alcohol intake.

This article was translated from the Medscape Portuguese edition. A version appeared on Medscape.com.

In recent weeks, you may have noticed some familiar headlines about red wine and cardiovascular health. Why the sudden return of these stories? Because of an article recently published in the American Journal of Clinical Nutrition.

Funded in part by a grant from the São Paulo Research Foundation (FAPESP), the “Wine Flora Study” was carried out by prominent researchers from institutions in South America, Europe, and the United States: University of São Paulo; State University of Campinas, São Paulo; University of Brasília; University of Verona (Italy); Austrian Institute of Technology, Tulln; and Harvard Medical School, Boston. The team looked into the effects of red wine on gut flora and plasma levels of trimethylamine-N-oxide (TMAO). And what they found was quite interesting.
 

The study

Previous results have pointed to the beneficial effect that red wine has on the gut microbiome.

The Wine Flora Study involved 42 men (average age, 60 years) with documented coronary artery disease. The trial encompassed two 3-week interventions. In one, the participants consumed 250 mL of red wine per day; the red wine sample had an alcohol content (% v) of 12.75. The Brazilian Wine Institute produced and supplied the red wine: a 2014 Merlot bottled in August 2016 and customized for the study. The second intervention involved alcohol abstention.

Each intervention was preceded by a 2-week washout period. Because certain foods and drinks could interfere with the results, the participants were instructed not to consume alcoholic beverages, fermented foods (yogurt, kombucha, soy lecithin, kefir, sauerkraut, and other fermented vegetables), synthetic prebiotics (insulin, fructooligosaccharides), fiber, dairy, food polyphenols (grapes, grape juice, cranberries, strawberries), and probiotics.

At each intervention, the gut microbiota was analyzed via 16S ribosomal RNA highthroughput sequencing. This method makes it possible to identify bacterial species. The plasma metabolome of 20 randomly selected participants was evaluated by ultra–high-performance liquid chromatography with tandem mass spectrometry. In this method, liquid chromatography separates the compounds, and a mass spectrometer is used to analyze them.

One of the metabolites of interest was TMAO, which is produced from the trimethylamine released when gut bacteria process protein-rich foods. TMAO has been identified as playing a role in the development of atherosclerosis.
 

Results

After red wine consumption, there was significant remodeling of the gut microbiota, with a difference in beta diversity and predominance of Parasutterella, Ruminococcaceae, several Bacteroides species, and Prevotella.

Plasma metabolomic analysis revealed significant changes in metabolites after red wine consumption, consistent with improved redox homeostasis, which is involved in the oxidative stress that promotes atherosclerosis.

Plasma TMAO, however, did not differ between red wine intervention and alcohol abstention.
 

Implications

The researchers concluded that modulation of the gut microbiota may contribute to the putative cardiovascular benefits of moderate red wine consumption. But, as they were careful to point out in the very title of the study, a red wine intervention does not modify plasma TMAO. They also mentioned that the 3-week period may have been too short for the findings to serve as the basis for promoting any meaningful modification. In addition, the team emphasized that these data remain hypothesisgenerating and pave the way for future research.

In an interview with FAPESP, the study’s corresponding author, Protásio Lemos da Luz, MD, PhD, warned about the risks associated with drinking too much alcohol (> 8.5 oz., or 250 mL, of wine daily).

It should be kept in mind that, in Brazil, people do not drink nearly as much wine as they do beer or liquor. Furthermore, the evidence that is available does not provide confirmation of the existence or the extent of the protective health effects associated with light or moderate alcohol intake.

This article was translated from the Medscape Portuguese edition. A version appeared on Medscape.com.

In recent weeks, you may have noticed some familiar headlines about red wine and cardiovascular health. Why the sudden return of these stories? Because of an article recently published in the American Journal of Clinical Nutrition.

Funded in part by a grant from the São Paulo Research Foundation (FAPESP), the “Wine Flora Study” was carried out by prominent researchers from institutions in South America, Europe, and the United States: University of São Paulo; State University of Campinas, São Paulo; University of Brasília; University of Verona (Italy); Austrian Institute of Technology, Tulln; and Harvard Medical School, Boston. The team looked into the effects of red wine on gut flora and plasma levels of trimethylamine-N-oxide (TMAO). And what they found was quite interesting.
 

The study

Previous results have pointed to the beneficial effect that red wine has on the gut microbiome.

The Wine Flora Study involved 42 men (average age, 60 years) with documented coronary artery disease. The trial encompassed two 3-week interventions. In one, the participants consumed 250 mL of red wine per day; the red wine sample had an alcohol content (% v) of 12.75. The Brazilian Wine Institute produced and supplied the red wine: a 2014 Merlot bottled in August 2016 and customized for the study. The second intervention involved alcohol abstention.

Each intervention was preceded by a 2-week washout period. Because certain foods and drinks could interfere with the results, the participants were instructed not to consume alcoholic beverages, fermented foods (yogurt, kombucha, soy lecithin, kefir, sauerkraut, and other fermented vegetables), synthetic prebiotics (insulin, fructooligosaccharides), fiber, dairy, food polyphenols (grapes, grape juice, cranberries, strawberries), and probiotics.

At each intervention, the gut microbiota was analyzed via 16S ribosomal RNA highthroughput sequencing. This method makes it possible to identify bacterial species. The plasma metabolome of 20 randomly selected participants was evaluated by ultra–high-performance liquid chromatography with tandem mass spectrometry. In this method, liquid chromatography separates the compounds, and a mass spectrometer is used to analyze them.

One of the metabolites of interest was TMAO, which is produced from the trimethylamine released when gut bacteria process protein-rich foods. TMAO has been identified as playing a role in the development of atherosclerosis.
 

Results

After red wine consumption, there was significant remodeling of the gut microbiota, with a difference in beta diversity and predominance of Parasutterella, Ruminococcaceae, several Bacteroides species, and Prevotella.

Plasma metabolomic analysis revealed significant changes in metabolites after red wine consumption, consistent with improved redox homeostasis, which is involved in the oxidative stress that promotes atherosclerosis.

Plasma TMAO, however, did not differ between red wine intervention and alcohol abstention.
 

Implications

The researchers concluded that modulation of the gut microbiota may contribute to the putative cardiovascular benefits of moderate red wine consumption. But, as they were careful to point out in the very title of the study, a red wine intervention does not modify plasma TMAO. They also mentioned that the 3-week period may have been too short for the findings to serve as the basis for promoting any meaningful modification. In addition, the team emphasized that these data remain hypothesisgenerating and pave the way for future research.

In an interview with FAPESP, the study’s corresponding author, Protásio Lemos da Luz, MD, PhD, warned about the risks associated with drinking too much alcohol (> 8.5 oz., or 250 mL, of wine daily).

It should be kept in mind that, in Brazil, people do not drink nearly as much wine as they do beer or liquor. Furthermore, the evidence that is available does not provide confirmation of the existence or the extent of the protective health effects associated with light or moderate alcohol intake.

This article was translated from the Medscape Portuguese edition. A version appeared on Medscape.com.

Bacterial proteins in the bleeding gums of patients with periodontal disease (PD) and rheumatoid arthritis (RA) enter the bloodstream and trigger immune responses that may contribute to RA pathogenesis and disease flares, a new longitudinal study suggests.

The results suggest that PD involves repeated oral mucosa breakdowns with the release of citrullinated oral bacteria into the bloodstream and that these bacteria activate inflammatory monocytes in the inflamed RA synovium and in the blood of patients with RA. The bacteria also activate anti-citrullinated protein antibody (ACPA)–positive B cells, promoting affinity maturation and epitope spreading to citrullinated human antigens, the authors wrote.

“Our study discovered frequent and repeated episodes of oral bacteria in the blood of patients with periodontal disease and rheumatoid arthritis,” senior study author Dana E. Orange, MD, associate professor of clinical investigation at Rockefeller University, New York, said in an interview. “We saw that these bacteria were triggering an inflammatory [monocyte] response that is similar to what we see in the inflamed joints of patients with RA.

“RA patients are less likely to benefit from RA treatment if they have concurrent periodontal disease,” she said.

“RA patients tend to harbor cyclic citrullinated peptide [CCP] autoantibodies. Many groups have noted that CCP antibodies are very highly mutated, a signature of a B-cell/antibody response that has been stimulated over and over again,” Dr. Orange explained. “We found that CCP antibodies also bind the same oral bacteria we detected in the bloodstream. That patients with PD experience frequent, repeated episodes of oral bacteria in the blood is consistent with the very high level of mutation burden of CCP antibodies.”
 

Periodontal disease is a large problem among older adults

Periodontal disease ranges from gingivitis with swollen, red gums that may bleed, to periodontitis with gums pulling away from teeth, bone loss, and loose or lost teeth. PD is very prevalent in the United States, with some form of it occurring in 47% of people 30 years of age and older and in 70% of those 65 years and older, according to the Centers for Disease Control and Prevention.

PD is more common in people with RA who have detectable ACPAs, and that link implicates oral mucosal inflammation in RA pathogenesis.
 

Investigating whether PD leads to RA

At Rockefeller University, Dr. Orange and her colleagues followed five female patients with RA who were seropositive for CCP over the course of 1-4 years. Two had severe PD, and three showed no signs of PD. Each week, participants provided finger-stick blood samples for RNA sequencing and B-cell repertoire sequencing, reported changes in their medication and dental work, and completed questionnaires. They also underwent monthly physical exams that evaluated tenderness and swelling in 28 joints, and they provided additional samples during self-reported flares.

At Stanford (Calif.) University, researchers isolated plasmablasts from blood samples collected from 12 donors with anti-CPP+ RA and healthy donors. They also analyzed synovial fluid samples from 65 RA and OA patients.

In addition, University of Colorado researchers collected plasma samples from patients with RA and healthy donors, and they classified the gingival health of participants.

The researchers found that the patients with PD also had repeated flare-ups of oral bacteria in the blood, mainly from the Streptococcaceae family, suggesting that the oral mucosa repeatedly broke down and introduced bacteria into the bloodstream. In the blood, inflammatory immune cells targeted the bacteria and released ACPAs, which have been linked with RA.

“Even without dental procedures, patients with RA and periodontal disease experience repeated episodes of bacteremia,” Dr. Orange said. “While dental procedures are known to be associated with dissemination of oral bacteria into the bloodstream, we didn’t expect to see this happening so frequently and independent of dental procedures. We also had thought that people with oral bacteria in their blood would have symptoms such as fever or malaise, but they were asymptomatic.”
 

Experts welcome the results

“It is well established that oral health impacts overall health. In particular, the link between periodontal disease and chronic systemic diseases has been explored in many robust studies,” Chi T. Viet, MD, DDS, PhD, oral and maxillofacial surgeon and associate professor at the Loma Linda (Calif.) University School of Dentistry, told this news organization.

“The study ... highlights the importance of early treatment and prevention of oral health issues, as they can have devastating systemic sequelae,” added Dr. Viet, who was not involved in the study.

Devon Charlton, MD, MPH, director of rheumatology at the University of Pittsburgh Medical Center Regional Orthopedics in New Castle, Pa., advised patients and providers to team up to manage RA and PD.

“If the patient and provider aggressively treat periodontal disease and dental health in general, the patient decreases their risk of infection and inflammation, decreases the potential development of RA, and increases their future quality of life,” said Dr. Charlton, also not involved in the study.

However, findings from the study population may be difficult to generalize to other populations, he added.

Dr. Orange and her colleagues suggest further related research, including studies on whether treating PD makes RA easier to treat and whether the treatment of PD in patients whose RA is in clinical remission raises the likelihood of being able to discontinue therapy safely.

The study was supported through grant funding from the National Institutes of Health, the National Science Foundation, the Robertson Foundation, Rockefeller University, the Bernard and Irene Schwartz Foundation, the Iris and Junming Le Foundation, and the Rheumatology Research Foundation. Dr. Orange reports no relevant financial relationships. Several coauthors report financial relationships with the pharmaceutical industry. Dr. Viet and Dr. Charlton report no relevant financial relationships. All experts commented by email.

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

Bacterial proteins in the bleeding gums of patients with periodontal disease (PD) and rheumatoid arthritis (RA) enter the bloodstream and trigger immune responses that may contribute to RA pathogenesis and disease flares, a new longitudinal study suggests.

The results suggest that PD involves repeated oral mucosa breakdowns with the release of citrullinated oral bacteria into the bloodstream and that these bacteria activate inflammatory monocytes in the inflamed RA synovium and in the blood of patients with RA. The bacteria also activate anti-citrullinated protein antibody (ACPA)–positive B cells, promoting affinity maturation and epitope spreading to citrullinated human antigens, the authors wrote.

“Our study discovered frequent and repeated episodes of oral bacteria in the blood of patients with periodontal disease and rheumatoid arthritis,” senior study author Dana E. Orange, MD, associate professor of clinical investigation at Rockefeller University, New York, said in an interview. “We saw that these bacteria were triggering an inflammatory [monocyte] response that is similar to what we see in the inflamed joints of patients with RA.

“RA patients are less likely to benefit from RA treatment if they have concurrent periodontal disease,” she said.

“RA patients tend to harbor cyclic citrullinated peptide [CCP] autoantibodies. Many groups have noted that CCP antibodies are very highly mutated, a signature of a B-cell/antibody response that has been stimulated over and over again,” Dr. Orange explained. “We found that CCP antibodies also bind the same oral bacteria we detected in the bloodstream. That patients with PD experience frequent, repeated episodes of oral bacteria in the blood is consistent with the very high level of mutation burden of CCP antibodies.”
 

Periodontal disease is a large problem among older adults

Periodontal disease ranges from gingivitis with swollen, red gums that may bleed, to periodontitis with gums pulling away from teeth, bone loss, and loose or lost teeth. PD is very prevalent in the United States, with some form of it occurring in 47% of people 30 years of age and older and in 70% of those 65 years and older, according to the Centers for Disease Control and Prevention.

PD is more common in people with RA who have detectable ACPAs, and that link implicates oral mucosal inflammation in RA pathogenesis.
 

Investigating whether PD leads to RA

At Rockefeller University, Dr. Orange and her colleagues followed five female patients with RA who were seropositive for CCP over the course of 1-4 years. Two had severe PD, and three showed no signs of PD. Each week, participants provided finger-stick blood samples for RNA sequencing and B-cell repertoire sequencing, reported changes in their medication and dental work, and completed questionnaires. They also underwent monthly physical exams that evaluated tenderness and swelling in 28 joints, and they provided additional samples during self-reported flares.

At Stanford (Calif.) University, researchers isolated plasmablasts from blood samples collected from 12 donors with anti-CPP+ RA and healthy donors. They also analyzed synovial fluid samples from 65 RA and OA patients.

In addition, University of Colorado researchers collected plasma samples from patients with RA and healthy donors, and they classified the gingival health of participants.

The researchers found that the patients with PD also had repeated flare-ups of oral bacteria in the blood, mainly from the Streptococcaceae family, suggesting that the oral mucosa repeatedly broke down and introduced bacteria into the bloodstream. In the blood, inflammatory immune cells targeted the bacteria and released ACPAs, which have been linked with RA.

“Even without dental procedures, patients with RA and periodontal disease experience repeated episodes of bacteremia,” Dr. Orange said. “While dental procedures are known to be associated with dissemination of oral bacteria into the bloodstream, we didn’t expect to see this happening so frequently and independent of dental procedures. We also had thought that people with oral bacteria in their blood would have symptoms such as fever or malaise, but they were asymptomatic.”
 

Experts welcome the results

“It is well established that oral health impacts overall health. In particular, the link between periodontal disease and chronic systemic diseases has been explored in many robust studies,” Chi T. Viet, MD, DDS, PhD, oral and maxillofacial surgeon and associate professor at the Loma Linda (Calif.) University School of Dentistry, told this news organization.

“The study ... highlights the importance of early treatment and prevention of oral health issues, as they can have devastating systemic sequelae,” added Dr. Viet, who was not involved in the study.

Devon Charlton, MD, MPH, director of rheumatology at the University of Pittsburgh Medical Center Regional Orthopedics in New Castle, Pa., advised patients and providers to team up to manage RA and PD.

“If the patient and provider aggressively treat periodontal disease and dental health in general, the patient decreases their risk of infection and inflammation, decreases the potential development of RA, and increases their future quality of life,” said Dr. Charlton, also not involved in the study.

However, findings from the study population may be difficult to generalize to other populations, he added.

Dr. Orange and her colleagues suggest further related research, including studies on whether treating PD makes RA easier to treat and whether the treatment of PD in patients whose RA is in clinical remission raises the likelihood of being able to discontinue therapy safely.

The study was supported through grant funding from the National Institutes of Health, the National Science Foundation, the Robertson Foundation, Rockefeller University, the Bernard and Irene Schwartz Foundation, the Iris and Junming Le Foundation, and the Rheumatology Research Foundation. Dr. Orange reports no relevant financial relationships. Several coauthors report financial relationships with the pharmaceutical industry. Dr. Viet and Dr. Charlton report no relevant financial relationships. All experts commented by email.

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

Bacterial proteins in the bleeding gums of patients with periodontal disease (PD) and rheumatoid arthritis (RA) enter the bloodstream and trigger immune responses that may contribute to RA pathogenesis and disease flares, a new longitudinal study suggests.

The results suggest that PD involves repeated oral mucosa breakdowns with the release of citrullinated oral bacteria into the bloodstream and that these bacteria activate inflammatory monocytes in the inflamed RA synovium and in the blood of patients with RA. The bacteria also activate anti-citrullinated protein antibody (ACPA)–positive B cells, promoting affinity maturation and epitope spreading to citrullinated human antigens, the authors wrote.

“Our study discovered frequent and repeated episodes of oral bacteria in the blood of patients with periodontal disease and rheumatoid arthritis,” senior study author Dana E. Orange, MD, associate professor of clinical investigation at Rockefeller University, New York, said in an interview. “We saw that these bacteria were triggering an inflammatory [monocyte] response that is similar to what we see in the inflamed joints of patients with RA.

“RA patients are less likely to benefit from RA treatment if they have concurrent periodontal disease,” she said.

“RA patients tend to harbor cyclic citrullinated peptide [CCP] autoantibodies. Many groups have noted that CCP antibodies are very highly mutated, a signature of a B-cell/antibody response that has been stimulated over and over again,” Dr. Orange explained. “We found that CCP antibodies also bind the same oral bacteria we detected in the bloodstream. That patients with PD experience frequent, repeated episodes of oral bacteria in the blood is consistent with the very high level of mutation burden of CCP antibodies.”
 

Periodontal disease is a large problem among older adults

Periodontal disease ranges from gingivitis with swollen, red gums that may bleed, to periodontitis with gums pulling away from teeth, bone loss, and loose or lost teeth. PD is very prevalent in the United States, with some form of it occurring in 47% of people 30 years of age and older and in 70% of those 65 years and older, according to the Centers for Disease Control and Prevention.

PD is more common in people with RA who have detectable ACPAs, and that link implicates oral mucosal inflammation in RA pathogenesis.
 

Investigating whether PD leads to RA

At Rockefeller University, Dr. Orange and her colleagues followed five female patients with RA who were seropositive for CCP over the course of 1-4 years. Two had severe PD, and three showed no signs of PD. Each week, participants provided finger-stick blood samples for RNA sequencing and B-cell repertoire sequencing, reported changes in their medication and dental work, and completed questionnaires. They also underwent monthly physical exams that evaluated tenderness and swelling in 28 joints, and they provided additional samples during self-reported flares.

At Stanford (Calif.) University, researchers isolated plasmablasts from blood samples collected from 12 donors with anti-CPP+ RA and healthy donors. They also analyzed synovial fluid samples from 65 RA and OA patients.

In addition, University of Colorado researchers collected plasma samples from patients with RA and healthy donors, and they classified the gingival health of participants.

The researchers found that the patients with PD also had repeated flare-ups of oral bacteria in the blood, mainly from the Streptococcaceae family, suggesting that the oral mucosa repeatedly broke down and introduced bacteria into the bloodstream. In the blood, inflammatory immune cells targeted the bacteria and released ACPAs, which have been linked with RA.

“Even without dental procedures, patients with RA and periodontal disease experience repeated episodes of bacteremia,” Dr. Orange said. “While dental procedures are known to be associated with dissemination of oral bacteria into the bloodstream, we didn’t expect to see this happening so frequently and independent of dental procedures. We also had thought that people with oral bacteria in their blood would have symptoms such as fever or malaise, but they were asymptomatic.”
 

Experts welcome the results

“It is well established that oral health impacts overall health. In particular, the link between periodontal disease and chronic systemic diseases has been explored in many robust studies,” Chi T. Viet, MD, DDS, PhD, oral and maxillofacial surgeon and associate professor at the Loma Linda (Calif.) University School of Dentistry, told this news organization.

“The study ... highlights the importance of early treatment and prevention of oral health issues, as they can have devastating systemic sequelae,” added Dr. Viet, who was not involved in the study.

Devon Charlton, MD, MPH, director of rheumatology at the University of Pittsburgh Medical Center Regional Orthopedics in New Castle, Pa., advised patients and providers to team up to manage RA and PD.

“If the patient and provider aggressively treat periodontal disease and dental health in general, the patient decreases their risk of infection and inflammation, decreases the potential development of RA, and increases their future quality of life,” said Dr. Charlton, also not involved in the study.

However, findings from the study population may be difficult to generalize to other populations, he added.

Dr. Orange and her colleagues suggest further related research, including studies on whether treating PD makes RA easier to treat and whether the treatment of PD in patients whose RA is in clinical remission raises the likelihood of being able to discontinue therapy safely.

The study was supported through grant funding from the National Institutes of Health, the National Science Foundation, the Robertson Foundation, Rockefeller University, the Bernard and Irene Schwartz Foundation, the Iris and Junming Le Foundation, and the Rheumatology Research Foundation. Dr. Orange reports no relevant financial relationships. Several coauthors report financial relationships with the pharmaceutical industry. Dr. Viet and Dr. Charlton report no relevant financial relationships. All experts commented by email.

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

The patient is sent for lymphoscintigraphy, which showed impaired lymphatic drainage of both lower extremities consistent with obesity-induced lymphedema. 

Lymphedema is a chronic condition caused by the abnormal development of the lymphatic system (primary lymphedema) or injury to lymphatic vasculature (secondary lymphedema). Chronic interstitial fluid accumulation may lead to fibrosis, persistent inflammation, and adipose deposition, which often results in massive hypertrophy. Obesity, which affects approximately 40% of the US population, is a rising cause of secondary lymphedema. Obesity-induced lymphedema (OIL) is a result of external compression of the lymphatic system by adipose tissue and increased production of lymph, which results in direct injury to the lymphatic endothelium. As BMI increases, lymphedema worsens and ambulation becomes more difficult, placing patients in an unfavorable cycle of weight gain and lymphatic injury. 

The diagnosis of OIL is made by history and physical and is confirmed with diagnostic imaging. The classic presentation of lymphedema is edema of the lower extremities and a positive Stemmer sign. The Stemmer sign is positive if the examiner is unable to grab the dorsal skin between the thumb and index finger. The gold standard for lymphatic imaging is radionuclide lymphoscintigraphy. It involves injecting a tracer protein into the distal extremity, which should be taken up by the lymphatic vasculature and visualized in patients with normal lymphatic function. Lymphoscintigraphy has a high sensitivity (96%) and specificity (100%) for the diagnosis of lymphedema. 

The risk for lymphatic dysfunction increases with elevated BMI. A BMI threshold appears to exist between 53 and 59, at which point lower-extremity lymphatic dysfunction begins to occur and is almost universal when BMI exceeds 60. Sixty percent of patients with OIL will develop massive localized lymphedema; the higher the BMI, the greater the risk for massive localized lymphedema. Typical areas of localized lymphedema include the lower extremities, genitals, and abdominal wall. In addition, patients with OIL are at increased risk for infections, such as cellulitis. Other complications of OIL include functional disabilities, psychosocial morbidity, and malignant transformation. 

Patients at risk for OIL should be counseled and educated about weight management interventions, such as intensive treatment programs, lifestyle changes, and medications before their BMI reaches 50, a threshold where irreversible lower-extremity lymphedema may occur. Although weight loss may reduce symptoms of OIL, irreversible lymphatic dysfunction also may occur. Individuals at risk for OIL are often referred to a bariatric surgical weight management center. 

Lymphedema management consists of compression regimens, physiotherapy, and manual lymphatic drainage. Adipose deposition in the late stages of lymphedema may decrease the response to such manual treatments. Operative procedures are typically used when these treatment options have been inadequate. Patients with chronic advanced lymphedema, in whom lymphatic impairment is accompanied by deposition of fibroadipose tissue, may also require debulking surgery. 

Courtney Whittle, MD, MSW, Diplomate of ABOM, Pediatric Lead, Obesity Champion, TSPMG, Weight A Minute Clinic, Atlanta, Georgia.

Courtney Whittle, MD, MSW, Diplomate of ABOM, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

The patient is sent for lymphoscintigraphy, which showed impaired lymphatic drainage of both lower extremities consistent with obesity-induced lymphedema. 

Lymphedema is a chronic condition caused by the abnormal development of the lymphatic system (primary lymphedema) or injury to lymphatic vasculature (secondary lymphedema). Chronic interstitial fluid accumulation may lead to fibrosis, persistent inflammation, and adipose deposition, which often results in massive hypertrophy. Obesity, which affects approximately 40% of the US population, is a rising cause of secondary lymphedema. Obesity-induced lymphedema (OIL) is a result of external compression of the lymphatic system by adipose tissue and increased production of lymph, which results in direct injury to the lymphatic endothelium. As BMI increases, lymphedema worsens and ambulation becomes more difficult, placing patients in an unfavorable cycle of weight gain and lymphatic injury. 

The diagnosis of OIL is made by history and physical and is confirmed with diagnostic imaging. The classic presentation of lymphedema is edema of the lower extremities and a positive Stemmer sign. The Stemmer sign is positive if the examiner is unable to grab the dorsal skin between the thumb and index finger. The gold standard for lymphatic imaging is radionuclide lymphoscintigraphy. It involves injecting a tracer protein into the distal extremity, which should be taken up by the lymphatic vasculature and visualized in patients with normal lymphatic function. Lymphoscintigraphy has a high sensitivity (96%) and specificity (100%) for the diagnosis of lymphedema. 

The risk for lymphatic dysfunction increases with elevated BMI. A BMI threshold appears to exist between 53 and 59, at which point lower-extremity lymphatic dysfunction begins to occur and is almost universal when BMI exceeds 60. Sixty percent of patients with OIL will develop massive localized lymphedema; the higher the BMI, the greater the risk for massive localized lymphedema. Typical areas of localized lymphedema include the lower extremities, genitals, and abdominal wall. In addition, patients with OIL are at increased risk for infections, such as cellulitis. Other complications of OIL include functional disabilities, psychosocial morbidity, and malignant transformation. 

Patients at risk for OIL should be counseled and educated about weight management interventions, such as intensive treatment programs, lifestyle changes, and medications before their BMI reaches 50, a threshold where irreversible lower-extremity lymphedema may occur. Although weight loss may reduce symptoms of OIL, irreversible lymphatic dysfunction also may occur. Individuals at risk for OIL are often referred to a bariatric surgical weight management center. 

Lymphedema management consists of compression regimens, physiotherapy, and manual lymphatic drainage. Adipose deposition in the late stages of lymphedema may decrease the response to such manual treatments. Operative procedures are typically used when these treatment options have been inadequate. Patients with chronic advanced lymphedema, in whom lymphatic impairment is accompanied by deposition of fibroadipose tissue, may also require debulking surgery. 

Courtney Whittle, MD, MSW, Diplomate of ABOM, Pediatric Lead, Obesity Champion, TSPMG, Weight A Minute Clinic, Atlanta, Georgia.

Courtney Whittle, MD, MSW, Diplomate of ABOM, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

The patient is sent for lymphoscintigraphy, which showed impaired lymphatic drainage of both lower extremities consistent with obesity-induced lymphedema. 

Lymphedema is a chronic condition caused by the abnormal development of the lymphatic system (primary lymphedema) or injury to lymphatic vasculature (secondary lymphedema). Chronic interstitial fluid accumulation may lead to fibrosis, persistent inflammation, and adipose deposition, which often results in massive hypertrophy. Obesity, which affects approximately 40% of the US population, is a rising cause of secondary lymphedema. Obesity-induced lymphedema (OIL) is a result of external compression of the lymphatic system by adipose tissue and increased production of lymph, which results in direct injury to the lymphatic endothelium. As BMI increases, lymphedema worsens and ambulation becomes more difficult, placing patients in an unfavorable cycle of weight gain and lymphatic injury. 

The diagnosis of OIL is made by history and physical and is confirmed with diagnostic imaging. The classic presentation of lymphedema is edema of the lower extremities and a positive Stemmer sign. The Stemmer sign is positive if the examiner is unable to grab the dorsal skin between the thumb and index finger. The gold standard for lymphatic imaging is radionuclide lymphoscintigraphy. It involves injecting a tracer protein into the distal extremity, which should be taken up by the lymphatic vasculature and visualized in patients with normal lymphatic function. Lymphoscintigraphy has a high sensitivity (96%) and specificity (100%) for the diagnosis of lymphedema. 

The risk for lymphatic dysfunction increases with elevated BMI. A BMI threshold appears to exist between 53 and 59, at which point lower-extremity lymphatic dysfunction begins to occur and is almost universal when BMI exceeds 60. Sixty percent of patients with OIL will develop massive localized lymphedema; the higher the BMI, the greater the risk for massive localized lymphedema. Typical areas of localized lymphedema include the lower extremities, genitals, and abdominal wall. In addition, patients with OIL are at increased risk for infections, such as cellulitis. Other complications of OIL include functional disabilities, psychosocial morbidity, and malignant transformation. 

Patients at risk for OIL should be counseled and educated about weight management interventions, such as intensive treatment programs, lifestyle changes, and medications before their BMI reaches 50, a threshold where irreversible lower-extremity lymphedema may occur. Although weight loss may reduce symptoms of OIL, irreversible lymphatic dysfunction also may occur. Individuals at risk for OIL are often referred to a bariatric surgical weight management center. 

Lymphedema management consists of compression regimens, physiotherapy, and manual lymphatic drainage. Adipose deposition in the late stages of lymphedema may decrease the response to such manual treatments. Operative procedures are typically used when these treatment options have been inadequate. Patients with chronic advanced lymphedema, in whom lymphatic impairment is accompanied by deposition of fibroadipose tissue, may also require debulking surgery. 

Courtney Whittle, MD, MSW, Diplomate of ABOM, Pediatric Lead, Obesity Champion, TSPMG, Weight A Minute Clinic, Atlanta, Georgia.

Courtney Whittle, MD, MSW, Diplomate of ABOM, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

How does endometriosis affect the whole body, and how often is it misunderstood for another condition?

Dr. Taylor: Far too often, we think about endometriosis as just a cause of bad menstrual cramps. So many times, we miss the signs and falsely attribute symptoms to other diseases. I cannot tell you the number of people who have seen multiple practitioners for other conditions, when the underlying problem was actually endometriosis.

Endometriosis affects the whole body. It can affect the intestines, the bladder, and body weight, and the brain and mood. Endometriosis causes fatigue and inflammation, and in the long run it can lead to an increased risk for cardiovascular disease. When we as physicians do surgery or laparoscopy, we find these little blue and brown lesions in the pelvis, and they certainly do cause pain, but that is not the whole disease.

Endometriosis heightens pain and nerve sensitivity for patients, and we should not dismiss the debilitating effect of these symptoms. Things actually do hurt more. In fact, the pain can spread from beyond the time of the menstrual period and spread to other areas besides the uterus.

We cannot ignore the totality of the effects of the disease and only focus on one part of the problem. More importantly, we cannot be distracted and discount endometriosis or mistake it for another condition. I have seen many patients who went to a gastroenterologist first and may even have had a colonoscopy because of some bowel symptoms, but then we come to find out it was endometriosis irritating the bowels at the time of their period and not another primary disease.

Another example is that the patient may see a urologist and have a cystoscopy to assess bladder pain, especially if the pain comes on around the time of menses. However, that pain is probably due to endometriosis irritating the bladder, not a primary bladder problem.

I have even had patients who were sent to a psychiatrist first because of anxiety that was actually being caused by the endometriosis. It is important to understand that treating the primary problem—endometriosis—should be our focus.

Which effects of this chronic disease can have the most long-term impact?

Dr. Taylor: It is important to understand that endometriosis has long-term effects on the entire body. For example, it affects the brain, increasing anxiety and depression. It causes pain sensitization, fatigue, and body inflammation. Endometriosis can also damage blood vessels or cause atherosclerosis.

A quick diagnosis is crucial because often this disease affects women at the most critical points in their life—either when they are in school, or in the early part of their career, when they need to be able to focus. It is important to get their endometriosis under control early and prevent long-term complications. Unfortunately, the long-term impacts are an aspect we do not focus on enough.

Infertility is another common long-term consequence of endometriosis. The sooner we can diagnose endometriosis, the sooner we can begin treatment and the more likely we can preserve someone's fertility. Our goal is to catch endometriosis early enough, preserve the patient’s fertility, and prevent any damage, so they hopefully will not have trouble getting pregnant or need medical intervention to get pregnant.

What methods do you use to diagnose endometriosis as quickly as possible?

Dr. Taylor: The sooner we can pinpoint the correct diagnosis and begin treatment, the more we can not only relieve patients of pain, but also stop that inflammation and all of these other manifestations of endometriosis so that they are not saddled with this for life.

We used to say you needed a laparoscopy to accurately diagnose endometriosis, and that statement is still true. You cannot see the most common types of endometriosis on an ultrasound or MRI. The endometriosis has to be pretty bad before you see it on an MRI or an ultrasound, and at that point it is often a big cyst in the ovary or a big nodule that is invasive.

However, you can diagnose endometriosis just by listening to your patients. If they have extremely painful menstrual cycles, dysmenorrhea, or painful menstrual cramps that get worse over the years, the problem is most likely endometriosis. You can rule out a few other things, and you can make that empiric clinical diagnosis of endometriosis. You can know with confidence that somebody likely has endometriosis. The treatments are benign. The first-line therapy would be to try a birth control pill. If we had to perform a laparoscopy before beginning endometriosis treatment, I think we would be doing our patients a huge disservice.

In addition to birth control pills, what are the most common therapeutic treatments you use in day-to-day practice?

Dr. Taylor: Birth control pills are still the first-line therapy. We use birth control pills because they are easy, well-tolerated, and inexpensive, but about a third of women will be resistant. Birth control pills are a great option when they work, but they do not always work 100% of the time.

We have a couple of other hormonal treatment options. Rarely, but occasionally, we use something called danazol, which is a mild male hormone. Side effects can be acne or hair growth, but it works well and is inexpensive. We used to give injectable agents, like leuprolide. Leuprolide is a harsh medication with once-a-month injections, and it puts someone in a temporary menopausal state with hot flashes and the possibility of decreased bone mineral density.

Today, we have the new class of GnRH antagonists that are a milder, gentler version of those injectable medications. They are oral, and you do not have to fully suppress estrogen levels all the way down to menopause. Patients can take the GnRH antagonists, stop treatment, and try to get pregnant at their next cycle.

Occasionally, we find that someone does not respond to any medical therapies, so surgery still has an important role. The usual reason for surgery is that you may suppress the active disease with medications, but the old damage is still there causing some pain, which can only be removed with surgery. Surgery is a good way to relieve that pain and it helps improve pregnancy rates for people with endometriosis wishing to conceive.

What does the future look like for endometriosis-related infertility, particularly related to in vitro fertilization (IVF)?

Dr. Taylor: We currently have an IVF trial in the works, in which we are using a hormone-suppressing GnRH (gonadotropin-releasing hormone) antagonist, elagolix, which suppresses endometriosis. The medication is administered before IVF. The goal is to determine if this approach leads to a better pregnancy rate in IVF cycles.

We are also working on nonhormonal medications in the laboratory, but these strategies are not yet ready for human clinical trials. These laboratory trials are investigating the basic biology of endometriosis, with the goal of learning what makes endometrial tissue grow in the wrong place, what makes it grow aggressively, and how it signals to other organs to cause damage.

We are looking at some additional nonhormonal medications that may possibly be used in someone trying to conceive, so that we can increase their chances of becoming pregnant. We are testing these medications in mice, but eventually we hope they progress to human clinical trials. The future for endometriosis therapy is nonhormonal treatments that can be used in somebody trying to conceive. That is what we have on the horizon.

Unfortunately for people with endometriosis wishing to conceive, all the classic first-line medications used to treat the condition are reproductive hormones that interfere with the ability to become pregnant. When we stop these medications, many women with endometriosis get pregnant spontaneously always suggest patients with endometriosis wishing to conceive try this approach, unless we know the endometriosis is very extensive. However, IVF is a good way to correct even the worst cases of endometriosis. As long as somebody has not waited until they are in their 40s and they have run out of eggs, IVF will usually correct endometriosis-related infertility.

Overall, how we treat endometriosis has been revolutionized and we have much better options than we had just 5 years ago. In my day-to-day practice, I recognize the importance of talking more openly about endometriosis, understanding the different symptoms, and not dismissing those connections. We should be able to talk about this important medical problem and all of its manifestations. I published a paper in The Lancet at the end of 2021 about the concept of endometriosis as a systemic whole-body disease and its effects. I think open conversations with patients about endometriosis is making a world of difference for the women with this disease.

How does endometriosis affect the whole body, and how often is it misunderstood for another condition?

Dr. Taylor: Far too often, we think about endometriosis as just a cause of bad menstrual cramps. So many times, we miss the signs and falsely attribute symptoms to other diseases. I cannot tell you the number of people who have seen multiple practitioners for other conditions, when the underlying problem was actually endometriosis.

Endometriosis affects the whole body. It can affect the intestines, the bladder, and body weight, and the brain and mood. Endometriosis causes fatigue and inflammation, and in the long run it can lead to an increased risk for cardiovascular disease. When we as physicians do surgery or laparoscopy, we find these little blue and brown lesions in the pelvis, and they certainly do cause pain, but that is not the whole disease.

Endometriosis heightens pain and nerve sensitivity for patients, and we should not dismiss the debilitating effect of these symptoms. Things actually do hurt more. In fact, the pain can spread from beyond the time of the menstrual period and spread to other areas besides the uterus.

We cannot ignore the totality of the effects of the disease and only focus on one part of the problem. More importantly, we cannot be distracted and discount endometriosis or mistake it for another condition. I have seen many patients who went to a gastroenterologist first and may even have had a colonoscopy because of some bowel symptoms, but then we come to find out it was endometriosis irritating the bowels at the time of their period and not another primary disease.

Another example is that the patient may see a urologist and have a cystoscopy to assess bladder pain, especially if the pain comes on around the time of menses. However, that pain is probably due to endometriosis irritating the bladder, not a primary bladder problem.

I have even had patients who were sent to a psychiatrist first because of anxiety that was actually being caused by the endometriosis. It is important to understand that treating the primary problem—endometriosis—should be our focus.

Which effects of this chronic disease can have the most long-term impact?

Dr. Taylor: It is important to understand that endometriosis has long-term effects on the entire body. For example, it affects the brain, increasing anxiety and depression. It causes pain sensitization, fatigue, and body inflammation. Endometriosis can also damage blood vessels or cause atherosclerosis.

A quick diagnosis is crucial because often this disease affects women at the most critical points in their life—either when they are in school, or in the early part of their career, when they need to be able to focus. It is important to get their endometriosis under control early and prevent long-term complications. Unfortunately, the long-term impacts are an aspect we do not focus on enough.

Infertility is another common long-term consequence of endometriosis. The sooner we can diagnose endometriosis, the sooner we can begin treatment and the more likely we can preserve someone's fertility. Our goal is to catch endometriosis early enough, preserve the patient’s fertility, and prevent any damage, so they hopefully will not have trouble getting pregnant or need medical intervention to get pregnant.

What methods do you use to diagnose endometriosis as quickly as possible?

Dr. Taylor: The sooner we can pinpoint the correct diagnosis and begin treatment, the more we can not only relieve patients of pain, but also stop that inflammation and all of these other manifestations of endometriosis so that they are not saddled with this for life.

We used to say you needed a laparoscopy to accurately diagnose endometriosis, and that statement is still true. You cannot see the most common types of endometriosis on an ultrasound or MRI. The endometriosis has to be pretty bad before you see it on an MRI or an ultrasound, and at that point it is often a big cyst in the ovary or a big nodule that is invasive.

However, you can diagnose endometriosis just by listening to your patients. If they have extremely painful menstrual cycles, dysmenorrhea, or painful menstrual cramps that get worse over the years, the problem is most likely endometriosis. You can rule out a few other things, and you can make that empiric clinical diagnosis of endometriosis. You can know with confidence that somebody likely has endometriosis. The treatments are benign. The first-line therapy would be to try a birth control pill. If we had to perform a laparoscopy before beginning endometriosis treatment, I think we would be doing our patients a huge disservice.

In addition to birth control pills, what are the most common therapeutic treatments you use in day-to-day practice?

Dr. Taylor: Birth control pills are still the first-line therapy. We use birth control pills because they are easy, well-tolerated, and inexpensive, but about a third of women will be resistant. Birth control pills are a great option when they work, but they do not always work 100% of the time.

We have a couple of other hormonal treatment options. Rarely, but occasionally, we use something called danazol, which is a mild male hormone. Side effects can be acne or hair growth, but it works well and is inexpensive. We used to give injectable agents, like leuprolide. Leuprolide is a harsh medication with once-a-month injections, and it puts someone in a temporary menopausal state with hot flashes and the possibility of decreased bone mineral density.

Today, we have the new class of GnRH antagonists that are a milder, gentler version of those injectable medications. They are oral, and you do not have to fully suppress estrogen levels all the way down to menopause. Patients can take the GnRH antagonists, stop treatment, and try to get pregnant at their next cycle.

Occasionally, we find that someone does not respond to any medical therapies, so surgery still has an important role. The usual reason for surgery is that you may suppress the active disease with medications, but the old damage is still there causing some pain, which can only be removed with surgery. Surgery is a good way to relieve that pain and it helps improve pregnancy rates for people with endometriosis wishing to conceive.

What does the future look like for endometriosis-related infertility, particularly related to in vitro fertilization (IVF)?

Dr. Taylor: We currently have an IVF trial in the works, in which we are using a hormone-suppressing GnRH (gonadotropin-releasing hormone) antagonist, elagolix, which suppresses endometriosis. The medication is administered before IVF. The goal is to determine if this approach leads to a better pregnancy rate in IVF cycles.

We are also working on nonhormonal medications in the laboratory, but these strategies are not yet ready for human clinical trials. These laboratory trials are investigating the basic biology of endometriosis, with the goal of learning what makes endometrial tissue grow in the wrong place, what makes it grow aggressively, and how it signals to other organs to cause damage.

We are looking at some additional nonhormonal medications that may possibly be used in someone trying to conceive, so that we can increase their chances of becoming pregnant. We are testing these medications in mice, but eventually we hope they progress to human clinical trials. The future for endometriosis therapy is nonhormonal treatments that can be used in somebody trying to conceive. That is what we have on the horizon.

Unfortunately for people with endometriosis wishing to conceive, all the classic first-line medications used to treat the condition are reproductive hormones that interfere with the ability to become pregnant. When we stop these medications, many women with endometriosis get pregnant spontaneously always suggest patients with endometriosis wishing to conceive try this approach, unless we know the endometriosis is very extensive. However, IVF is a good way to correct even the worst cases of endometriosis. As long as somebody has not waited until they are in their 40s and they have run out of eggs, IVF will usually correct endometriosis-related infertility.

Overall, how we treat endometriosis has been revolutionized and we have much better options than we had just 5 years ago. In my day-to-day practice, I recognize the importance of talking more openly about endometriosis, understanding the different symptoms, and not dismissing those connections. We should be able to talk about this important medical problem and all of its manifestations. I published a paper in The Lancet at the end of 2021 about the concept of endometriosis as a systemic whole-body disease and its effects. I think open conversations with patients about endometriosis is making a world of difference for the women with this disease.

How does endometriosis affect the whole body, and how often is it misunderstood for another condition?

Dr. Taylor: Far too often, we think about endometriosis as just a cause of bad menstrual cramps. So many times, we miss the signs and falsely attribute symptoms to other diseases. I cannot tell you the number of people who have seen multiple practitioners for other conditions, when the underlying problem was actually endometriosis.

Endometriosis affects the whole body. It can affect the intestines, the bladder, and body weight, and the brain and mood. Endometriosis causes fatigue and inflammation, and in the long run it can lead to an increased risk for cardiovascular disease. When we as physicians do surgery or laparoscopy, we find these little blue and brown lesions in the pelvis, and they certainly do cause pain, but that is not the whole disease.

Endometriosis heightens pain and nerve sensitivity for patients, and we should not dismiss the debilitating effect of these symptoms. Things actually do hurt more. In fact, the pain can spread from beyond the time of the menstrual period and spread to other areas besides the uterus.

We cannot ignore the totality of the effects of the disease and only focus on one part of the problem. More importantly, we cannot be distracted and discount endometriosis or mistake it for another condition. I have seen many patients who went to a gastroenterologist first and may even have had a colonoscopy because of some bowel symptoms, but then we come to find out it was endometriosis irritating the bowels at the time of their period and not another primary disease.

Another example is that the patient may see a urologist and have a cystoscopy to assess bladder pain, especially if the pain comes on around the time of menses. However, that pain is probably due to endometriosis irritating the bladder, not a primary bladder problem.

I have even had patients who were sent to a psychiatrist first because of anxiety that was actually being caused by the endometriosis. It is important to understand that treating the primary problem—endometriosis—should be our focus.

Which effects of this chronic disease can have the most long-term impact?

Dr. Taylor: It is important to understand that endometriosis has long-term effects on the entire body. For example, it affects the brain, increasing anxiety and depression. It causes pain sensitization, fatigue, and body inflammation. Endometriosis can also damage blood vessels or cause atherosclerosis.

A quick diagnosis is crucial because often this disease affects women at the most critical points in their life—either when they are in school, or in the early part of their career, when they need to be able to focus. It is important to get their endometriosis under control early and prevent long-term complications. Unfortunately, the long-term impacts are an aspect we do not focus on enough.

Infertility is another common long-term consequence of endometriosis. The sooner we can diagnose endometriosis, the sooner we can begin treatment and the more likely we can preserve someone's fertility. Our goal is to catch endometriosis early enough, preserve the patient’s fertility, and prevent any damage, so they hopefully will not have trouble getting pregnant or need medical intervention to get pregnant.

What methods do you use to diagnose endometriosis as quickly as possible?

Dr. Taylor: The sooner we can pinpoint the correct diagnosis and begin treatment, the more we can not only relieve patients of pain, but also stop that inflammation and all of these other manifestations of endometriosis so that they are not saddled with this for life.

We used to say you needed a laparoscopy to accurately diagnose endometriosis, and that statement is still true. You cannot see the most common types of endometriosis on an ultrasound or MRI. The endometriosis has to be pretty bad before you see it on an MRI or an ultrasound, and at that point it is often a big cyst in the ovary or a big nodule that is invasive.

However, you can diagnose endometriosis just by listening to your patients. If they have extremely painful menstrual cycles, dysmenorrhea, or painful menstrual cramps that get worse over the years, the problem is most likely endometriosis. You can rule out a few other things, and you can make that empiric clinical diagnosis of endometriosis. You can know with confidence that somebody likely has endometriosis. The treatments are benign. The first-line therapy would be to try a birth control pill. If we had to perform a laparoscopy before beginning endometriosis treatment, I think we would be doing our patients a huge disservice.

In addition to birth control pills, what are the most common therapeutic treatments you use in day-to-day practice?

Dr. Taylor: Birth control pills are still the first-line therapy. We use birth control pills because they are easy, well-tolerated, and inexpensive, but about a third of women will be resistant. Birth control pills are a great option when they work, but they do not always work 100% of the time.

We have a couple of other hormonal treatment options. Rarely, but occasionally, we use something called danazol, which is a mild male hormone. Side effects can be acne or hair growth, but it works well and is inexpensive. We used to give injectable agents, like leuprolide. Leuprolide is a harsh medication with once-a-month injections, and it puts someone in a temporary menopausal state with hot flashes and the possibility of decreased bone mineral density.

Today, we have the new class of GnRH antagonists that are a milder, gentler version of those injectable medications. They are oral, and you do not have to fully suppress estrogen levels all the way down to menopause. Patients can take the GnRH antagonists, stop treatment, and try to get pregnant at their next cycle.

Occasionally, we find that someone does not respond to any medical therapies, so surgery still has an important role. The usual reason for surgery is that you may suppress the active disease with medications, but the old damage is still there causing some pain, which can only be removed with surgery. Surgery is a good way to relieve that pain and it helps improve pregnancy rates for people with endometriosis wishing to conceive.

What does the future look like for endometriosis-related infertility, particularly related to in vitro fertilization (IVF)?

Dr. Taylor: We currently have an IVF trial in the works, in which we are using a hormone-suppressing GnRH (gonadotropin-releasing hormone) antagonist, elagolix, which suppresses endometriosis. The medication is administered before IVF. The goal is to determine if this approach leads to a better pregnancy rate in IVF cycles.

We are also working on nonhormonal medications in the laboratory, but these strategies are not yet ready for human clinical trials. These laboratory trials are investigating the basic biology of endometriosis, with the goal of learning what makes endometrial tissue grow in the wrong place, what makes it grow aggressively, and how it signals to other organs to cause damage.

We are looking at some additional nonhormonal medications that may possibly be used in someone trying to conceive, so that we can increase their chances of becoming pregnant. We are testing these medications in mice, but eventually we hope they progress to human clinical trials. The future for endometriosis therapy is nonhormonal treatments that can be used in somebody trying to conceive. That is what we have on the horizon.

Unfortunately for people with endometriosis wishing to conceive, all the classic first-line medications used to treat the condition are reproductive hormones that interfere with the ability to become pregnant. When we stop these medications, many women with endometriosis get pregnant spontaneously always suggest patients with endometriosis wishing to conceive try this approach, unless we know the endometriosis is very extensive. However, IVF is a good way to correct even the worst cases of endometriosis. As long as somebody has not waited until they are in their 40s and they have run out of eggs, IVF will usually correct endometriosis-related infertility.

Overall, how we treat endometriosis has been revolutionized and we have much better options than we had just 5 years ago. In my day-to-day practice, I recognize the importance of talking more openly about endometriosis, understanding the different symptoms, and not dismissing those connections. We should be able to talk about this important medical problem and all of its manifestations. I published a paper in The Lancet at the end of 2021 about the concept of endometriosis as a systemic whole-body disease and its effects. I think open conversations with patients about endometriosis is making a world of difference for the women with this disease.

HONOLULU – Combining cryotherapy, salicylic acid, and fluorouracil (5-FU) can improve the efficacy of treating common warts, but topical or intralesional cidofovir may be required for recalcitrant lesions or those located in areas that are challenging to treat, according to John S. Barbieri, MD, MBA.

“There are 5 million office visits per year in the United States for warts and molluscum, and they’re most common in pediatrics,” Dr. Barbieri, of the department of dermatology at Brigham and Women’s Hospital, Boston, said at the Hawaii Dermatology Seminar provided by MedscapeLIVE! “In fact, some studies have suggested that one in three children in primary school suffers from warts.”

Doug Brunk/MDedge News

According to a 2012 Cochrane review of topical therapies for warts, first-line treatments such as salicylic acid, cryotherapy, 5-FU, or Candida antigen injection often have modest efficacy when used alone. For example, the authors found that salicylic acid and cryotherapy cleared warts in about 60%-70% of cases, respectively, but clearance rates were improved by combining the two therapies.

In an earlier literature review and meta-analysis, investigators evaluated the effect of 5-FU plus salicylic acid or salicylic acid alone. The therapeutic effect for common warts across all studies was a 63.4% response rate (complete healing) for 5-FU/SA vversus 23.1% for the 5-FU–free controls, respectively. For plantar warts, the response rate was 63% versus 11%, respectively.

“But what about the person with multiple warts or those in challenging locations where you might worry about destructive treatments hurting the nail fold or causing nail dystrophy?” Dr. Barbieri asked. “Maybe they’ve used salicylic acid or intralesional Candida and they’re still not getting better. What can we do for these patients?”

Emerging research suggests that topical cidofovir can be a valuable option for recalcitrant warts or those in sensitive locations. In a case report of a 10-year-old boy with more than 50 severe verrucous papules on his hands and face that were recalcitrant to multiple conventional therapies, topical 1% cidofovir applied daily for 8 weeks was effective, with no adverse side effects. A young female patient who presented to Dr. Barbieri with multiple warts around the nail matrix of several fingers experienced complete clearance after treatment with topical cidofovir, he said. Other researchers found this approach to be effective for plantar warts as well, in a report of two brothers with severe combined immunodeficiency after hematopoietic stem cell transplantation with persistent warts that did not respond to traditional topical treatments.

David Carillet/Dreamstime

“Topical cidofovir is typically a painless treatment, which is nice, especially for our pediatric patients who might be afraid of other therapies like or cryotherapy or intralesional injections,” One limitation is that it is “a bit expensive,” Dr. Barbieri said. “To have topical cidofovir compounded is typically $100-$300, depending on the quantity and strength that you ask for.”

Intralesional cidofovir is another treatment option. In a retrospective study of 58 patients, Dr. Barbieri and colleagues evaluated the outcome of intralesional cidofovir treatment of warts in immunocompromised and nonimmunocompromised patients. Rates of improvement ranged from 98.3% to 100%, while resolution rates ranged from 75.9% to 97.6%.

“Most of the patients had warts for more than 5 years and almost half of them had recalcitrant warts,” Dr. Barbieri said. “These were mostly adult patients, but I think this is a treatment that can work in younger populations as well. About 10%-15% had HIV or cancer or diabetes or were transplant recipients, but despite these challenges and despite these recalcitrant warts, about 100% had improvement.”

He pointed out that cidofovir is available as a 75 mg/mL vial that comes with a 5 mL single-use vial. He dilutes this with normal saline to create a 15 mg/mL solution.

“If you want to be efficient you can try to schedule multiple patients together on the same day as a single vial is sufficient to treat about 25 patients,” assuming about 1 mL is injected per patient, he said. “The challenge with intralesional cidofovir is that it’s painful beyond just the needle part of the injection. Sometimes a nerve block can be helpful. But this can be an effective treatment for patients with recalcitrant warts or those with comorbidities.”

Other intralesional therapies to try for recalcitrant warts, he said, include bleomycin (1 U/mL solution, 1-2 mL per treatment, spaced every 2-4 weeks), and 5-FU (a 4:1 mixture of 5-FU [50 mg/mL] and 2% lidocaine).

Dr. Barbieri disclosed that he receives consulting fees from Dexcel for work unrelated to his presentation. Medscape and this news organization are owned by the same parent company.

HONOLULU – Combining cryotherapy, salicylic acid, and fluorouracil (5-FU) can improve the efficacy of treating common warts, but topical or intralesional cidofovir may be required for recalcitrant lesions or those located in areas that are challenging to treat, according to John S. Barbieri, MD, MBA.

“There are 5 million office visits per year in the United States for warts and molluscum, and they’re most common in pediatrics,” Dr. Barbieri, of the department of dermatology at Brigham and Women’s Hospital, Boston, said at the Hawaii Dermatology Seminar provided by MedscapeLIVE! “In fact, some studies have suggested that one in three children in primary school suffers from warts.”

Doug Brunk/MDedge News

According to a 2012 Cochrane review of topical therapies for warts, first-line treatments such as salicylic acid, cryotherapy, 5-FU, or Candida antigen injection often have modest efficacy when used alone. For example, the authors found that salicylic acid and cryotherapy cleared warts in about 60%-70% of cases, respectively, but clearance rates were improved by combining the two therapies.

In an earlier literature review and meta-analysis, investigators evaluated the effect of 5-FU plus salicylic acid or salicylic acid alone. The therapeutic effect for common warts across all studies was a 63.4% response rate (complete healing) for 5-FU/SA vversus 23.1% for the 5-FU–free controls, respectively. For plantar warts, the response rate was 63% versus 11%, respectively.

“But what about the person with multiple warts or those in challenging locations where you might worry about destructive treatments hurting the nail fold or causing nail dystrophy?” Dr. Barbieri asked. “Maybe they’ve used salicylic acid or intralesional Candida and they’re still not getting better. What can we do for these patients?”

Emerging research suggests that topical cidofovir can be a valuable option for recalcitrant warts or those in sensitive locations. In a case report of a 10-year-old boy with more than 50 severe verrucous papules on his hands and face that were recalcitrant to multiple conventional therapies, topical 1% cidofovir applied daily for 8 weeks was effective, with no adverse side effects. A young female patient who presented to Dr. Barbieri with multiple warts around the nail matrix of several fingers experienced complete clearance after treatment with topical cidofovir, he said. Other researchers found this approach to be effective for plantar warts as well, in a report of two brothers with severe combined immunodeficiency after hematopoietic stem cell transplantation with persistent warts that did not respond to traditional topical treatments.

David Carillet/Dreamstime

“Topical cidofovir is typically a painless treatment, which is nice, especially for our pediatric patients who might be afraid of other therapies like or cryotherapy or intralesional injections,” One limitation is that it is “a bit expensive,” Dr. Barbieri said. “To have topical cidofovir compounded is typically $100-$300, depending on the quantity and strength that you ask for.”

Intralesional cidofovir is another treatment option. In a retrospective study of 58 patients, Dr. Barbieri and colleagues evaluated the outcome of intralesional cidofovir treatment of warts in immunocompromised and nonimmunocompromised patients. Rates of improvement ranged from 98.3% to 100%, while resolution rates ranged from 75.9% to 97.6%.

“Most of the patients had warts for more than 5 years and almost half of them had recalcitrant warts,” Dr. Barbieri said. “These were mostly adult patients, but I think this is a treatment that can work in younger populations as well. About 10%-15% had HIV or cancer or diabetes or were transplant recipients, but despite these challenges and despite these recalcitrant warts, about 100% had improvement.”

He pointed out that cidofovir is available as a 75 mg/mL vial that comes with a 5 mL single-use vial. He dilutes this with normal saline to create a 15 mg/mL solution.

“If you want to be efficient you can try to schedule multiple patients together on the same day as a single vial is sufficient to treat about 25 patients,” assuming about 1 mL is injected per patient, he said. “The challenge with intralesional cidofovir is that it’s painful beyond just the needle part of the injection. Sometimes a nerve block can be helpful. But this can be an effective treatment for patients with recalcitrant warts or those with comorbidities.”

Other intralesional therapies to try for recalcitrant warts, he said, include bleomycin (1 U/mL solution, 1-2 mL per treatment, spaced every 2-4 weeks), and 5-FU (a 4:1 mixture of 5-FU [50 mg/mL] and 2% lidocaine).

Dr. Barbieri disclosed that he receives consulting fees from Dexcel for work unrelated to his presentation. Medscape and this news organization are owned by the same parent company.

HONOLULU – Combining cryotherapy, salicylic acid, and fluorouracil (5-FU) can improve the efficacy of treating common warts, but topical or intralesional cidofovir may be required for recalcitrant lesions or those located in areas that are challenging to treat, according to John S. Barbieri, MD, MBA.

“There are 5 million office visits per year in the United States for warts and molluscum, and they’re most common in pediatrics,” Dr. Barbieri, of the department of dermatology at Brigham and Women’s Hospital, Boston, said at the Hawaii Dermatology Seminar provided by MedscapeLIVE! “In fact, some studies have suggested that one in three children in primary school suffers from warts.”

Doug Brunk/MDedge News

According to a 2012 Cochrane review of topical therapies for warts, first-line treatments such as salicylic acid, cryotherapy, 5-FU, or Candida antigen injection often have modest efficacy when used alone. For example, the authors found that salicylic acid and cryotherapy cleared warts in about 60%-70% of cases, respectively, but clearance rates were improved by combining the two therapies.

In an earlier literature review and meta-analysis, investigators evaluated the effect of 5-FU plus salicylic acid or salicylic acid alone. The therapeutic effect for common warts across all studies was a 63.4% response rate (complete healing) for 5-FU/SA vversus 23.1% for the 5-FU–free controls, respectively. For plantar warts, the response rate was 63% versus 11%, respectively.

“But what about the person with multiple warts or those in challenging locations where you might worry about destructive treatments hurting the nail fold or causing nail dystrophy?” Dr. Barbieri asked. “Maybe they’ve used salicylic acid or intralesional Candida and they’re still not getting better. What can we do for these patients?”

Emerging research suggests that topical cidofovir can be a valuable option for recalcitrant warts or those in sensitive locations. In a case report of a 10-year-old boy with more than 50 severe verrucous papules on his hands and face that were recalcitrant to multiple conventional therapies, topical 1% cidofovir applied daily for 8 weeks was effective, with no adverse side effects. A young female patient who presented to Dr. Barbieri with multiple warts around the nail matrix of several fingers experienced complete clearance after treatment with topical cidofovir, he said. Other researchers found this approach to be effective for plantar warts as well, in a report of two brothers with severe combined immunodeficiency after hematopoietic stem cell transplantation with persistent warts that did not respond to traditional topical treatments.

David Carillet/Dreamstime

“Topical cidofovir is typically a painless treatment, which is nice, especially for our pediatric patients who might be afraid of other therapies like or cryotherapy or intralesional injections,” One limitation is that it is “a bit expensive,” Dr. Barbieri said. “To have topical cidofovir compounded is typically $100-$300, depending on the quantity and strength that you ask for.”

Intralesional cidofovir is another treatment option. In a retrospective study of 58 patients, Dr. Barbieri and colleagues evaluated the outcome of intralesional cidofovir treatment of warts in immunocompromised and nonimmunocompromised patients. Rates of improvement ranged from 98.3% to 100%, while resolution rates ranged from 75.9% to 97.6%.

“Most of the patients had warts for more than 5 years and almost half of them had recalcitrant warts,” Dr. Barbieri said. “These were mostly adult patients, but I think this is a treatment that can work in younger populations as well. About 10%-15% had HIV or cancer or diabetes or were transplant recipients, but despite these challenges and despite these recalcitrant warts, about 100% had improvement.”

He pointed out that cidofovir is available as a 75 mg/mL vial that comes with a 5 mL single-use vial. He dilutes this with normal saline to create a 15 mg/mL solution.

“If you want to be efficient you can try to schedule multiple patients together on the same day as a single vial is sufficient to treat about 25 patients,” assuming about 1 mL is injected per patient, he said. “The challenge with intralesional cidofovir is that it’s painful beyond just the needle part of the injection. Sometimes a nerve block can be helpful. But this can be an effective treatment for patients with recalcitrant warts or those with comorbidities.”

Other intralesional therapies to try for recalcitrant warts, he said, include bleomycin (1 U/mL solution, 1-2 mL per treatment, spaced every 2-4 weeks), and 5-FU (a 4:1 mixture of 5-FU [50 mg/mL] and 2% lidocaine).

Dr. Barbieri disclosed that he receives consulting fees from Dexcel for work unrelated to his presentation. Medscape and this news organization are owned by the same parent company.