Hand-wringing stories about the opioid epidemic are flooding the popular press – and clincians are seeing the headlines reflected in their practices.

As clinics fill with more and more pregnant patients who have opioid use disorder, both ob.gyns. and family physicians who incorporate obstetrics are facing a steep learning curve in dealing with the medical and ethical challenges these patients bring to their clinic visits. Though there’s no panacea, collaboration with community and family stakeholders and a comprehensive care model incorporating best practices can optimize outcomes for these fragile patients.

On May 23, 2016, the American College of Obstetricians and Gynecologists (ACOG) issued a statement affirming medically assisted treatment (MAT) as the recommended standard of care for pregnant women with opioid use disorders. In a statement, Hal Lawrence, MD, ACOG’s executive vice president and CEO, said, “Robust evidence has demonstrated that maintenance therapy during pregnancy can improve outcomes.”

Methadone has been the mainstay MAT medication, in part because its long time on the market means that favorable data are more robust than for buprenorphine. For patients in rural areas facing transportation challenges, however, or for those whose jobs or caregiving duties make a daily visit to a methadone clinic difficult, buprenorphine may be the better option. Additionally, especially in smaller communities, an oral self-administered medication avoids the obvious stigma of methadone clinic visits.

In making efforts to reduce maternal opioid dependence a 2016 legislative priority, ACOG voiced opposition to any legislation that might be punitive for women with opioid use disorder, as well as for babies born with neonatal abstinence syndrome; however, ACOG also supports public health efforts to reduce these conditions.

Wanda Filer, MD, president of the American Academy of Family Physicians, concurred in an interview. “We do not support criminalization or incarceration of pregnant women with substance use disorders,” stressed Dr. Filer, who noted that the AAFP does not have a formal policy statement at this point.

Courtesy AAFP News

Mishka Terplan, MD, an ob.gyn. who also is an addiction medicine specialist and has helped shape ACOG policy in this area, said in an interview that the maternal-fetal-placental unit has a “complicated and unique biology.” About targeted legislation – or reinterpretation of existing legislation – that incarcerates pregnant women with substance use disorder, he said, “These laws in effect cleave that unit. … To me, it’s unnatural, and not in the interests of the mom.”

Most laws that target women who are pregnant and have substance use disorder are on the state rather than the federal level, said Dr. Terplan, medical director of Behavioral Health System Baltimore.

Currently, three states allow involuntary commitment for treatment of pregnant women with substance use disorder, he said. Other states will classify substance use in pregnancy as child abuse, or use “chemical endangerment” statutes as a vehicle for incarceration or prosecution. Additionally, Medicaid provisions or limitations on access to MAT may vary by state, so physicians must be familiar with their local legal landscape in these cases, he said.

Community resources, critical to providing holistic care for this fragile population, are also region specific. In interviews, two physicians caring for pregnant women with opioid use disorder talked about how their practices are tailored to their communities. Understanding which resources are available and what’s possible for their patients informs how they care for these challenging patients.

La Crosse, Wis., is situated along the eastern side of the Mississippi River, close to the Minnesota-Iowa border. Though the college town has about 100,000 people in its urban area, the surrounding area gets very rural, very quickly. Gundersen Health System, based in La Crosse, has over two dozen clinics and a handful of hospitals in three states and is the practice home for Charles Schauberger, MD, an ob.gyn. who specializes in caring for pregnant women with substance use disorder.

Dr. Schauberger sees a broad range of patients with a wide demographic and urban-rural mix. He estimates that about two-thirds of his patients have a history of previous treatment for substance use disorder, while the opioid use is a fairly new development in other one-third. And most of them face many other challenges. “Many of my patients have high concerns about housing insecurity. They do a lot of couchsurfing,” said Dr. Schauberger.

His patient panel’s high no-show rate reflects the chaotic lives and transportation challenges of many of his patients, and it’s not uncommon for Dr. Schauberger’s patients to come from jail to his office for prenatal care. “It’s about not putting up barriers” for these women, he said. “I might see one patient for just one prenatal visit. Another one, we might see 20 times. We take what we can get.” His staff and partners all realize that flexibility is key to maximizing the chance for a good outcome, he said.

Using a collaborative care model, Dr. Schauberger and his nonphysician colleagues will see patients together. “We’ll often have two or three staff members in the room – at least the social worker, the care coordinator, and myself,” he said. Recognizing that “the patient, not the doctor, is at the center of the care model” is critical for making things work, he said. “It’s important for everyone on the team to be aware of that.”

The collaborative model helps to address the many nonmedical challenges that can contribute to ongoing issues with substance use. Family dynamics and the presence – or absence – of a support system can make a big difference in adherence to a treatment plan during pregnancy and in the postpartum period. “The social, political, and legal issues are really what are important. … We try to get them into the system as soon as possible,” he said. His practice has a close connection with the addiction team at Gundersen Health, which dispenses methadone, as does a private addiction clinic in town, said Dr. Schauberger, who prescribes buprenorphine.

Wisconsin is one of the three states where pregnant women can be committed for coerced treatment, said Dr. Terplan. Dr. Schauberger has a good connection with his legal system locally, and he views any possibility of incarceration or commitment for substance use in pregnancy as “a serious problem that we need to avoid.”

Not all physicians practice in an environment where they have the luxury of specialization, and Dr. Schauberger said that the demand is too high in many places for primary care providers not to manage the care of pregnant women with substance use disorders. Though these women are high risk, “it is a type of high risk that a family medicine doctor should be able to take care of without problem. Primarily the risks are premature labor and intrauterine growth retardation, which are both problems that most family medicine doctors that do obstetrics should be able to identify and follow,” he said.

This fits with the mission of family practice, said Dr. Filer. As a specialty, “family practice is tied in to community resources,” she said. “Knowing your referral network is vital.” She also sees a growing trend of AAFP members who have completed addiction medicine fellowships. “This reflects a practice need – and a community need,” she said.

One family practice physician’s rural southeast Nebraska practice necessitates a creative and flexible approach to caring for pregnant women with opioid use disorder. Robert Wergin, MD, the only physician in the small town of Milford, Neb., has a cradle-to-grave practice that includes obstetrics. When on call, he’s also the emergency physician at the 25-bed critical-access hospital that serves his area. The opioid epidemic touches his pregnant patients frequently.

Dr. Wergin is the current board chair of AAFP, as well as a past president of the organization. A Nebraska native, he draws his resources from the community, often tapping local pastors for help. He recently referred a pregnant woman to a church food pantry, since her food aid for the month had run out and she had another 10 days to face with an empty larder. “You’ve got to look at the comprehensive picture, and really know the patient to understand barriers to care, such as transportation problems and poverty.”

The area has no methadone clinic, and the few buprenorphine prescribers in the area usually have full practices and waiting lists. This means that optimal MAT may not be achievable. When he can, he sends patients to Lincoln, Neb., about 30 miles away, for treatment. If that’s not feasible, and the problem is identified early in the pregnancy, Dr. Wergin may help patients taper to eliminate or reduce opioid use.

An opinion reaffirmed in 2014 by ACOG recognized that MAT may not be accessible to all. ACOG’s Committee on Health Care for Underserved Women, together with the American Society of Addiction Medicine, wrote, “If the alternative to medically supervised withdrawal is continued illicit drug use, then a medically supervised withdrawal in the first trimester is preferable to waiting until the second trimester.”

Dr. Wergin also works hard to incorporate family supports into his care of substance-using pregnant women. “Comprehensive care is really important,” he said. “Somehow, you have to get a buy-in from the patient,” and sometimes a supportive mother or partner can make a big difference in maternal and neonatal outcomes, he explained. Rapport and trust are critical, and his career-long presence in the community has helped build that trust with the families for whom he cares, he said.

Planning for delivery of an infant who’s likely to exhibit neonatal abstinence syndrome is a particular challenge for Dr. Wergin. His local hospital has a staff of generalist nurses, no NICU, and no ventilators appropriate for critically ill infants. Optimally, there’s time for transport to a tertiary care center in Lincoln before delivery. Inevitably, though, some deliveries can’t wait. “If you’ve got a withdrawing baby, the earlier they get to a higher level of care, the better,” said Dr. Wergin. “You have to prepare as best you can, and coordinate a transfer soon.”

Dr. Filer said that the real value proposition offered by family physicians in addressing the social and medical complexity of substance use in pregnancy is the wrap-around care the specialty offers. “We can leverage the family and support systems … to help these women find a way to become whole again – whole in their work, in their family, in parenting,” she said.

Hand-wringing stories about the opioid epidemic are flooding the popular press – and clincians are seeing the headlines reflected in their practices.

As clinics fill with more and more pregnant patients who have opioid use disorder, both ob.gyns. and family physicians who incorporate obstetrics are facing a steep learning curve in dealing with the medical and ethical challenges these patients bring to their clinic visits. Though there’s no panacea, collaboration with community and family stakeholders and a comprehensive care model incorporating best practices can optimize outcomes for these fragile patients.

On May 23, 2016, the American College of Obstetricians and Gynecologists (ACOG) issued a statement affirming medically assisted treatment (MAT) as the recommended standard of care for pregnant women with opioid use disorders. In a statement, Hal Lawrence, MD, ACOG’s executive vice president and CEO, said, “Robust evidence has demonstrated that maintenance therapy during pregnancy can improve outcomes.”

Methadone has been the mainstay MAT medication, in part because its long time on the market means that favorable data are more robust than for buprenorphine. For patients in rural areas facing transportation challenges, however, or for those whose jobs or caregiving duties make a daily visit to a methadone clinic difficult, buprenorphine may be the better option. Additionally, especially in smaller communities, an oral self-administered medication avoids the obvious stigma of methadone clinic visits.

In making efforts to reduce maternal opioid dependence a 2016 legislative priority, ACOG voiced opposition to any legislation that might be punitive for women with opioid use disorder, as well as for babies born with neonatal abstinence syndrome; however, ACOG also supports public health efforts to reduce these conditions.

Wanda Filer, MD, president of the American Academy of Family Physicians, concurred in an interview. “We do not support criminalization or incarceration of pregnant women with substance use disorders,” stressed Dr. Filer, who noted that the AAFP does not have a formal policy statement at this point.

Courtesy AAFP News

Mishka Terplan, MD, an ob.gyn. who also is an addiction medicine specialist and has helped shape ACOG policy in this area, said in an interview that the maternal-fetal-placental unit has a “complicated and unique biology.” About targeted legislation – or reinterpretation of existing legislation – that incarcerates pregnant women with substance use disorder, he said, “These laws in effect cleave that unit. … To me, it’s unnatural, and not in the interests of the mom.”

Most laws that target women who are pregnant and have substance use disorder are on the state rather than the federal level, said Dr. Terplan, medical director of Behavioral Health System Baltimore.

Currently, three states allow involuntary commitment for treatment of pregnant women with substance use disorder, he said. Other states will classify substance use in pregnancy as child abuse, or use “chemical endangerment” statutes as a vehicle for incarceration or prosecution. Additionally, Medicaid provisions or limitations on access to MAT may vary by state, so physicians must be familiar with their local legal landscape in these cases, he said.

Community resources, critical to providing holistic care for this fragile population, are also region specific. In interviews, two physicians caring for pregnant women with opioid use disorder talked about how their practices are tailored to their communities. Understanding which resources are available and what’s possible for their patients informs how they care for these challenging patients.

La Crosse, Wis., is situated along the eastern side of the Mississippi River, close to the Minnesota-Iowa border. Though the college town has about 100,000 people in its urban area, the surrounding area gets very rural, very quickly. Gundersen Health System, based in La Crosse, has over two dozen clinics and a handful of hospitals in three states and is the practice home for Charles Schauberger, MD, an ob.gyn. who specializes in caring for pregnant women with substance use disorder.

Dr. Schauberger sees a broad range of patients with a wide demographic and urban-rural mix. He estimates that about two-thirds of his patients have a history of previous treatment for substance use disorder, while the opioid use is a fairly new development in other one-third. And most of them face many other challenges. “Many of my patients have high concerns about housing insecurity. They do a lot of couchsurfing,” said Dr. Schauberger.

His patient panel’s high no-show rate reflects the chaotic lives and transportation challenges of many of his patients, and it’s not uncommon for Dr. Schauberger’s patients to come from jail to his office for prenatal care. “It’s about not putting up barriers” for these women, he said. “I might see one patient for just one prenatal visit. Another one, we might see 20 times. We take what we can get.” His staff and partners all realize that flexibility is key to maximizing the chance for a good outcome, he said.

Using a collaborative care model, Dr. Schauberger and his nonphysician colleagues will see patients together. “We’ll often have two or three staff members in the room – at least the social worker, the care coordinator, and myself,” he said. Recognizing that “the patient, not the doctor, is at the center of the care model” is critical for making things work, he said. “It’s important for everyone on the team to be aware of that.”

The collaborative model helps to address the many nonmedical challenges that can contribute to ongoing issues with substance use. Family dynamics and the presence – or absence – of a support system can make a big difference in adherence to a treatment plan during pregnancy and in the postpartum period. “The social, political, and legal issues are really what are important. … We try to get them into the system as soon as possible,” he said. His practice has a close connection with the addiction team at Gundersen Health, which dispenses methadone, as does a private addiction clinic in town, said Dr. Schauberger, who prescribes buprenorphine.

Wisconsin is one of the three states where pregnant women can be committed for coerced treatment, said Dr. Terplan. Dr. Schauberger has a good connection with his legal system locally, and he views any possibility of incarceration or commitment for substance use in pregnancy as “a serious problem that we need to avoid.”

Not all physicians practice in an environment where they have the luxury of specialization, and Dr. Schauberger said that the demand is too high in many places for primary care providers not to manage the care of pregnant women with substance use disorders. Though these women are high risk, “it is a type of high risk that a family medicine doctor should be able to take care of without problem. Primarily the risks are premature labor and intrauterine growth retardation, which are both problems that most family medicine doctors that do obstetrics should be able to identify and follow,” he said.

This fits with the mission of family practice, said Dr. Filer. As a specialty, “family practice is tied in to community resources,” she said. “Knowing your referral network is vital.” She also sees a growing trend of AAFP members who have completed addiction medicine fellowships. “This reflects a practice need – and a community need,” she said.

One family practice physician’s rural southeast Nebraska practice necessitates a creative and flexible approach to caring for pregnant women with opioid use disorder. Robert Wergin, MD, the only physician in the small town of Milford, Neb., has a cradle-to-grave practice that includes obstetrics. When on call, he’s also the emergency physician at the 25-bed critical-access hospital that serves his area. The opioid epidemic touches his pregnant patients frequently.

Dr. Wergin is the current board chair of AAFP, as well as a past president of the organization. A Nebraska native, he draws his resources from the community, often tapping local pastors for help. He recently referred a pregnant woman to a church food pantry, since her food aid for the month had run out and she had another 10 days to face with an empty larder. “You’ve got to look at the comprehensive picture, and really know the patient to understand barriers to care, such as transportation problems and poverty.”

The area has no methadone clinic, and the few buprenorphine prescribers in the area usually have full practices and waiting lists. This means that optimal MAT may not be achievable. When he can, he sends patients to Lincoln, Neb., about 30 miles away, for treatment. If that’s not feasible, and the problem is identified early in the pregnancy, Dr. Wergin may help patients taper to eliminate or reduce opioid use.

An opinion reaffirmed in 2014 by ACOG recognized that MAT may not be accessible to all. ACOG’s Committee on Health Care for Underserved Women, together with the American Society of Addiction Medicine, wrote, “If the alternative to medically supervised withdrawal is continued illicit drug use, then a medically supervised withdrawal in the first trimester is preferable to waiting until the second trimester.”

Dr. Wergin also works hard to incorporate family supports into his care of substance-using pregnant women. “Comprehensive care is really important,” he said. “Somehow, you have to get a buy-in from the patient,” and sometimes a supportive mother or partner can make a big difference in maternal and neonatal outcomes, he explained. Rapport and trust are critical, and his career-long presence in the community has helped build that trust with the families for whom he cares, he said.

Planning for delivery of an infant who’s likely to exhibit neonatal abstinence syndrome is a particular challenge for Dr. Wergin. His local hospital has a staff of generalist nurses, no NICU, and no ventilators appropriate for critically ill infants. Optimally, there’s time for transport to a tertiary care center in Lincoln before delivery. Inevitably, though, some deliveries can’t wait. “If you’ve got a withdrawing baby, the earlier they get to a higher level of care, the better,” said Dr. Wergin. “You have to prepare as best you can, and coordinate a transfer soon.”

Dr. Filer said that the real value proposition offered by family physicians in addressing the social and medical complexity of substance use in pregnancy is the wrap-around care the specialty offers. “We can leverage the family and support systems … to help these women find a way to become whole again – whole in their work, in their family, in parenting,” she said.

Hand-wringing stories about the opioid epidemic are flooding the popular press – and clincians are seeing the headlines reflected in their practices.

As clinics fill with more and more pregnant patients who have opioid use disorder, both ob.gyns. and family physicians who incorporate obstetrics are facing a steep learning curve in dealing with the medical and ethical challenges these patients bring to their clinic visits. Though there’s no panacea, collaboration with community and family stakeholders and a comprehensive care model incorporating best practices can optimize outcomes for these fragile patients.

On May 23, 2016, the American College of Obstetricians and Gynecologists (ACOG) issued a statement affirming medically assisted treatment (MAT) as the recommended standard of care for pregnant women with opioid use disorders. In a statement, Hal Lawrence, MD, ACOG’s executive vice president and CEO, said, “Robust evidence has demonstrated that maintenance therapy during pregnancy can improve outcomes.”

Methadone has been the mainstay MAT medication, in part because its long time on the market means that favorable data are more robust than for buprenorphine. For patients in rural areas facing transportation challenges, however, or for those whose jobs or caregiving duties make a daily visit to a methadone clinic difficult, buprenorphine may be the better option. Additionally, especially in smaller communities, an oral self-administered medication avoids the obvious stigma of methadone clinic visits.

In making efforts to reduce maternal opioid dependence a 2016 legislative priority, ACOG voiced opposition to any legislation that might be punitive for women with opioid use disorder, as well as for babies born with neonatal abstinence syndrome; however, ACOG also supports public health efforts to reduce these conditions.

Wanda Filer, MD, president of the American Academy of Family Physicians, concurred in an interview. “We do not support criminalization or incarceration of pregnant women with substance use disorders,” stressed Dr. Filer, who noted that the AAFP does not have a formal policy statement at this point.

Courtesy AAFP News

Mishka Terplan, MD, an ob.gyn. who also is an addiction medicine specialist and has helped shape ACOG policy in this area, said in an interview that the maternal-fetal-placental unit has a “complicated and unique biology.” About targeted legislation – or reinterpretation of existing legislation – that incarcerates pregnant women with substance use disorder, he said, “These laws in effect cleave that unit. … To me, it’s unnatural, and not in the interests of the mom.”

Most laws that target women who are pregnant and have substance use disorder are on the state rather than the federal level, said Dr. Terplan, medical director of Behavioral Health System Baltimore.

Currently, three states allow involuntary commitment for treatment of pregnant women with substance use disorder, he said. Other states will classify substance use in pregnancy as child abuse, or use “chemical endangerment” statutes as a vehicle for incarceration or prosecution. Additionally, Medicaid provisions or limitations on access to MAT may vary by state, so physicians must be familiar with their local legal landscape in these cases, he said.

Community resources, critical to providing holistic care for this fragile population, are also region specific. In interviews, two physicians caring for pregnant women with opioid use disorder talked about how their practices are tailored to their communities. Understanding which resources are available and what’s possible for their patients informs how they care for these challenging patients.

La Crosse, Wis., is situated along the eastern side of the Mississippi River, close to the Minnesota-Iowa border. Though the college town has about 100,000 people in its urban area, the surrounding area gets very rural, very quickly. Gundersen Health System, based in La Crosse, has over two dozen clinics and a handful of hospitals in three states and is the practice home for Charles Schauberger, MD, an ob.gyn. who specializes in caring for pregnant women with substance use disorder.

Dr. Schauberger sees a broad range of patients with a wide demographic and urban-rural mix. He estimates that about two-thirds of his patients have a history of previous treatment for substance use disorder, while the opioid use is a fairly new development in other one-third. And most of them face many other challenges. “Many of my patients have high concerns about housing insecurity. They do a lot of couchsurfing,” said Dr. Schauberger.

His patient panel’s high no-show rate reflects the chaotic lives and transportation challenges of many of his patients, and it’s not uncommon for Dr. Schauberger’s patients to come from jail to his office for prenatal care. “It’s about not putting up barriers” for these women, he said. “I might see one patient for just one prenatal visit. Another one, we might see 20 times. We take what we can get.” His staff and partners all realize that flexibility is key to maximizing the chance for a good outcome, he said.

Using a collaborative care model, Dr. Schauberger and his nonphysician colleagues will see patients together. “We’ll often have two or three staff members in the room – at least the social worker, the care coordinator, and myself,” he said. Recognizing that “the patient, not the doctor, is at the center of the care model” is critical for making things work, he said. “It’s important for everyone on the team to be aware of that.”

The collaborative model helps to address the many nonmedical challenges that can contribute to ongoing issues with substance use. Family dynamics and the presence – or absence – of a support system can make a big difference in adherence to a treatment plan during pregnancy and in the postpartum period. “The social, political, and legal issues are really what are important. … We try to get them into the system as soon as possible,” he said. His practice has a close connection with the addiction team at Gundersen Health, which dispenses methadone, as does a private addiction clinic in town, said Dr. Schauberger, who prescribes buprenorphine.

Wisconsin is one of the three states where pregnant women can be committed for coerced treatment, said Dr. Terplan. Dr. Schauberger has a good connection with his legal system locally, and he views any possibility of incarceration or commitment for substance use in pregnancy as “a serious problem that we need to avoid.”

Not all physicians practice in an environment where they have the luxury of specialization, and Dr. Schauberger said that the demand is too high in many places for primary care providers not to manage the care of pregnant women with substance use disorders. Though these women are high risk, “it is a type of high risk that a family medicine doctor should be able to take care of without problem. Primarily the risks are premature labor and intrauterine growth retardation, which are both problems that most family medicine doctors that do obstetrics should be able to identify and follow,” he said.

This fits with the mission of family practice, said Dr. Filer. As a specialty, “family practice is tied in to community resources,” she said. “Knowing your referral network is vital.” She also sees a growing trend of AAFP members who have completed addiction medicine fellowships. “This reflects a practice need – and a community need,” she said.

One family practice physician’s rural southeast Nebraska practice necessitates a creative and flexible approach to caring for pregnant women with opioid use disorder. Robert Wergin, MD, the only physician in the small town of Milford, Neb., has a cradle-to-grave practice that includes obstetrics. When on call, he’s also the emergency physician at the 25-bed critical-access hospital that serves his area. The opioid epidemic touches his pregnant patients frequently.

Dr. Wergin is the current board chair of AAFP, as well as a past president of the organization. A Nebraska native, he draws his resources from the community, often tapping local pastors for help. He recently referred a pregnant woman to a church food pantry, since her food aid for the month had run out and she had another 10 days to face with an empty larder. “You’ve got to look at the comprehensive picture, and really know the patient to understand barriers to care, such as transportation problems and poverty.”

The area has no methadone clinic, and the few buprenorphine prescribers in the area usually have full practices and waiting lists. This means that optimal MAT may not be achievable. When he can, he sends patients to Lincoln, Neb., about 30 miles away, for treatment. If that’s not feasible, and the problem is identified early in the pregnancy, Dr. Wergin may help patients taper to eliminate or reduce opioid use.

An opinion reaffirmed in 2014 by ACOG recognized that MAT may not be accessible to all. ACOG’s Committee on Health Care for Underserved Women, together with the American Society of Addiction Medicine, wrote, “If the alternative to medically supervised withdrawal is continued illicit drug use, then a medically supervised withdrawal in the first trimester is preferable to waiting until the second trimester.”

Dr. Wergin also works hard to incorporate family supports into his care of substance-using pregnant women. “Comprehensive care is really important,” he said. “Somehow, you have to get a buy-in from the patient,” and sometimes a supportive mother or partner can make a big difference in maternal and neonatal outcomes, he explained. Rapport and trust are critical, and his career-long presence in the community has helped build that trust with the families for whom he cares, he said.

Planning for delivery of an infant who’s likely to exhibit neonatal abstinence syndrome is a particular challenge for Dr. Wergin. His local hospital has a staff of generalist nurses, no NICU, and no ventilators appropriate for critically ill infants. Optimally, there’s time for transport to a tertiary care center in Lincoln before delivery. Inevitably, though, some deliveries can’t wait. “If you’ve got a withdrawing baby, the earlier they get to a higher level of care, the better,” said Dr. Wergin. “You have to prepare as best you can, and coordinate a transfer soon.”

Dr. Filer said that the real value proposition offered by family physicians in addressing the social and medical complexity of substance use in pregnancy is the wrap-around care the specialty offers. “We can leverage the family and support systems … to help these women find a way to become whole again – whole in their work, in their family, in parenting,” she said.

Acne is a common and distressing condition that typically presents in adolescents and young adults and has been associated with not only medical but also emotional and aesthetic consequences. Acne treatments that offer faster improvement are the coveted goal. Although clinical studies support the use of combination therapy with topical retinoids and antibiotics, the overuse of antibiotics raises caution for bacterial resistance.1 Therefore, adjunctive treatments such as chemical peels, light therapy, and laser treatments can hasten the response to traditional acne treatments and in some cases may potentially decrease use of both oral and topical antibiotics.

Light therapy, particularly with visible light, may improve acne outcomes. Pneumatic broadband light (PBBL) is a light treatment in the broadband range (400–1200 nm) combined with a vacuum. The suction created by the vacuum has several effects on acne lesions, such as creating a mechanical lysis of thin-walled pustules and dislodging pore impaction. The blue light with a wavelength of 410 nm targets endogenous porphyrins in Propionibacterium acnes and elicits singlet oxygen production, resulting in bacterial destruction.^2,3 Studies showed that PBBL alone was effective in most patients with mild to moderate acne and caused minimal side effects.^2-4

We sought to determine if PBBL combined with a topical retinoid can accelerate and prolong acne improvement. We evaluated the efficacy, safety, and tolerability of PBBL plus adapalene gel 0.3% versus adapalene gel 0.3% monotherapy in patients with mild to moderate acne.

METHODSPatient Population

Patients with mild to moderate acne were eligible for the study if they were 18 years or older at screening, in good health, had stopped oral isotretinoin for at least 1 year prior to treatment initiation, and were not taking oral or topical antibiotics or using any topical retinoid derivatives for at least 1 month prior to treatment initiation. Inclusion criteria included at least 10 acne lesions on the face. Patients were excluded if they had a history of receiving PBBL treatment; had a history of scarring, hypopigmentation, or hyperpigmentation from laser or light treatments; and/or were pregnant or refused use of contraception during the study period.

Study Design

This single-blind, randomized, split-face study was approved by the institutional review board of the University of Pennsylvania (Philadelphia, Pennsylvania). All participants provided informed consent before entering the study. Each participant was randomly assigned to receive PBBL on one side of the face for 6 consecutive weeks and apply adapalene gel 0.3% to both sides of the face nightly for 10 weeks. Pneumatic broadband light treatment was performed using the following settings: starting power 2 (approximately 4–6 J/cm²) and vacuum setting 3 (negative pressure, approximately 3 lb/in²). The power setting was increased to a maximum of 6 (12–14 J/cm²) at subsequent visits depending on tolerability of the participants.

All participants visited the clinic weekly for 6 weeks and also returned for follow-up at week 10 (4 weeks following last PBBL treatment). At each visit, the participants completed satisfaction questionnaires and were assessed by a dermatologist evaluator using several parameters including the modified Global Acne Grading Score (mGAGS), clinical photography, participant self-assessment, physician assessment, and Wong Baker FACES Pain Rating Scale (WBPRS). The physician evaluator was blinded to the side of the face receiving PBBL treatment. Clinical photographs were taken to compare the clinical outcome at each visit versus baseline.

Efficacy Evaluation

Acne Counts

The blinded evaluator counted acne lesions and assessed the mGAGS at each visit prior to administration of the PBBL treatment. Acne lesions were counted separately as noninflammatory (comedones) and inflammatory (papules, pustules, nodules) on the forehead, cheeks, nose, and chin.

Modified Global Acne Grading Score

The modified Global Acne Grading Score was modified from the Global Acne Grading Scale (GAGS) that has previously been used to evaluate acne severity.⁵ The original GAGS used the type and location of the acne lesions. The GAGS considers 6 locations on the face, chest, and upper back, with a grading factor for each location (forehead=2; cheeks=2; nose=1; chin=1). Another grading factor represented the lesion type (0=no lesion; 1=comedone; 2=papule; 3=pustule; 4=nodule). The local score was calculated by multiplying the location grading factor by the lesion type grading factor. The total score was the sum of the individual local scores for the 4 locations.

Given that the number of acne lesions is important, we modified the GAGS by adding a grading factor that represented the number of lesions to improve the accuracy of the test (1=0–10 lesions; 2=11–20 lesions; 3=21–30 lesions; 4=≥31 lesions). The local score of mGAGS was calculated by multiplying the grading factors for location, lesion type, and number of lesions. Each local score was then added to yield a total score. The mGAGS may be useful and more accurate to determine the severity of acne (0=none; 1–44=mild; 45–80=moderate; 81–132=severe; 133–176=very severe).

Participant Self-assessment

Participants assessed their acne lesions using an 11-point rating scale (–5=100% worsening; –4=76%–99% worsening; –3=51%–75% worsening; –2=26%–50% worsening; –1=1%–25% worsening; 0=no improvement; 1=1%–25% improvement; 2=26%–50% improvement; 3=51%–75% improvement; 4=76%–99% improvement; 5=100% acne clear) to compare their acne at each treatment visit and week 10 follow-up with a baseline photograph.

Physician Assessment

The blinded evaluator assessed acne lesions on the face using the same 11-point rating scale that was used for participant self-assessment. For each participant, assessments were made at each treatment visit and week 10 follow-up by comparing baseline photographs.

Safety Evaluation

The WBPRS score, a standardized 6-point scale (0=no pain; 1=hurts a little bit; 2=hurts a little bit more; 3=hurts even more; 4=hurts whole lot; 5=hurt worst),⁶ was used to evaluate pain toleration during PBBL treatments and was recorded along with adverse events throughout the study.

Statistical Analysis

Based on data from 2 prior studies,3,7 we expected that the favorable clinical outcome of adapalene gel 0.3% and PBBL therapy would be 23% and 78%, respectively. If the adjunctive therapy with PBBL was beneficial, the favorable outcome would be higher than 78%. To be able to detect this difference, the sample size of 11 patients was needed when 5% type I error and 20% type II error were accepted.

Categorical variables were expressed as percentages, while continuous variables were expressed in terms of median (range). The clinical outcomes between both treatment groups were compared using the Wilcoxon signed rank test. A 2-tailed P value of ≤.05 was considered statistically significant. All statistical calculations were performed using STATA software version 10.0.

RESULTS
Baseline Characteristics

Four male and 7 female patients aged 18 to 35 years (median, 23 years) with mild to moderate acne were enrolled in the study. Of the 11 participants, 7 were white, 2 were black, 1 was Asian, and 1 was Latin American. Baseline characteristics of both sides of the face were comparable in all participants (Table 1). Eight participants (73%) completed the study. Two black participants withdrew from the study due to hyperpigmentation following PBBL treatment; 1 participant did not return for follow-up at week 10, as she was out of the country.

Lesion Counts

At week 3, reduction in noninflammatory lesions was significantly greater on the side receiving the combination therapy compared to the monotherapy side (P=.04)(Table 2). However, there was no significant difference between the combination therapy and the adapalene monotherapy sides in the reduction of noninflammatory and inflammatory lesions at week 4 (Figure 1). There was a remarkable improvement of the combination therapy and adapalene monotherapy sides in acne lesions, but there was no significant difference between the combination therapy and the adapalene monotherapy sides (Figure 2).

Modified Global Acne Grading Score

At weeks 3 and 4, the improvement of mGAGS was significantly greater on the side treated with the combination therapy (P=.05). However, this significant difference was not sustained (Table 3).

Participant Self-assessment and Physician Assessment

The rate of acne improvement according to participant self-assessment was slightly higher on the side receiving the combination therapy compared to the monotherapy side at week 2 (26%–50% vs 1%–25%) and week 6 (76%–99% vs 51%–75%). However, there was no statistically significant difference. For the physician assessment, there was no significant difference between the monotherapy and combination therapy sides.

Safety

The median WBPRS score was 1 (hurts a little bit) throughout all PBBL treatment visits. The maximum score was highest at week 1 (4=hurts whole lot) and subsequently decreased to 2 (hurts a little bit more) at week 6.

After the PBBL treatment, all participants experienced transient erythema in the treatment area. All participants noted their skin had become drier than usual from adapalene, except 1 participant (11%) who reported very dry skin on areas where adapalene gel 0.3% had been applied. However, the dryness was tolerable and relief was reported following application of a moisturizer. No participants withdrew from the study due to skin dryness.

Both black participants experienced hyperpigmentation caused by PBBL (1 on the treatment sites, the other on the test spot) and withdrew from the study. The hyperpigmentation resolved over time following application of a topical bleaching cream. One patient experienced purpura following PBBL treatment at week 4, which was associated with an increase in PBBL power. No other side effects (eg, scaling, stinging, burning, vesicle formation, blistering, crusting, scarring) were observed.

COMMENT

This 10-week study demonstrated that PBBL initially improved the appearance of acne in the first month of treatment, as determined by the significantly greater reduction in mGAGS for the combination side versus the adapalene monotherapy side. Differences in the reduction of acne lesions were not significant between the 2 treatments, except for noninflammatory lesion reduction at week 3. Analysis of physician assessment with photographs revealed acne improvement from baseline in the first month but no additional effects with the PBBL treatment at the end of study. Similarly, participant assessment indicated an improvement by week 2 with the combination therapy compared to adapalene monotherapy in their assessment of acne lesion reductions from baseline. By the end of the study, there was no significant difference between monotherapy and combination therapy.

These findings illustrate that combination therapy with PBBL plus adapalene improved the appearance of acne lesions within the first month of treatment, but there were no further signs of improvement at weeks 5 and 6. These results are consistent with at least 2 other studies that demonstrated acne reduction within the first 3 weeks of PBBL treatment.^2,4 The current study was completed as planned with 6 weeks of combination therapy and patients continued adapalene application until the last follow-up visit in week 10. The length of the combination treatment was enough to determine that extension of treatment would not be necessary to gain any further benefits in this study. Because of the small sample size, we would not be able to detect any significant differences, as the difference between the combination therapy and the adapalene monotherapy was less than 55%. Therefore, a future study with a larger sample size is needed to draw a better conclusion.

Pneumatic broadband light has shown impressive results in acne treatment. However, some side effects need to be considered. Minimal adverse events have been reported such as erythema, dryness, peeling, burning, and itching.^2-4 In this study, we found that all patients experienced transient erythema during and after PBBL treatment, but this effect disappeared in minutes. Purpura can occur if a higher power of PBBL is performed (6 or greater). Black patients experienced hyperpigmentation that can occur in darker skin types, as reported when light therapy is performed despite using the correct skin type tips.⁸ Therefore, care must be used in darker skin types, and we advocate a skin test in this population prior to general use.

Our study showed that PBBL can be safely combined with adapalene gel 0.3% and is well tolerated in the treatment of mild to moderate facial acne vulgaris for patients with Fitzpatrick skin types I to III. The combination of PBBL and adapalene reduces acne severity, as shown by the reduction in mGAGS during the first month of treatment. Patients noted faster improvement in their acne lesions with this combination. Although this study was limited by a relatively small sample size, this information may be useful in getting patients to be compliant overall, as they appeared to see results sooner, giving other therapies time to initiate their effect. It appears that 4 consecutive weekly treatments are enough to see that effect. Additionally, this combination therapy provides results without having to resort to oral antibiotics, as many patients today are concerned about creating future antibiotic resistance.

Conclusion

Adapalene gel 0.3% can be safely combined with PBBL for treatment of mild to moderate acne. Although the benefits of this combination therapy can be seen after 4 consecutive weekly treatments, the beneficial effect is not sustained.

Acknowledgment

The authors would like to thank Joyce Okawa, RN (Philadelphia, Pennsylvania), for her assistance in the submission to the University of Pennsylvania institutional review board.

Acne is a common and distressing condition that typically presents in adolescents and young adults and has been associated with not only medical but also emotional and aesthetic consequences. Acne treatments that offer faster improvement are the coveted goal. Although clinical studies support the use of combination therapy with topical retinoids and antibiotics, the overuse of antibiotics raises caution for bacterial resistance.1 Therefore, adjunctive treatments such as chemical peels, light therapy, and laser treatments can hasten the response to traditional acne treatments and in some cases may potentially decrease use of both oral and topical antibiotics.

Light therapy, particularly with visible light, may improve acne outcomes. Pneumatic broadband light (PBBL) is a light treatment in the broadband range (400–1200 nm) combined with a vacuum. The suction created by the vacuum has several effects on acne lesions, such as creating a mechanical lysis of thin-walled pustules and dislodging pore impaction. The blue light with a wavelength of 410 nm targets endogenous porphyrins in Propionibacterium acnes and elicits singlet oxygen production, resulting in bacterial destruction.^2,3 Studies showed that PBBL alone was effective in most patients with mild to moderate acne and caused minimal side effects.^2-4

We sought to determine if PBBL combined with a topical retinoid can accelerate and prolong acne improvement. We evaluated the efficacy, safety, and tolerability of PBBL plus adapalene gel 0.3% versus adapalene gel 0.3% monotherapy in patients with mild to moderate acne.

METHODSPatient Population

Patients with mild to moderate acne were eligible for the study if they were 18 years or older at screening, in good health, had stopped oral isotretinoin for at least 1 year prior to treatment initiation, and were not taking oral or topical antibiotics or using any topical retinoid derivatives for at least 1 month prior to treatment initiation. Inclusion criteria included at least 10 acne lesions on the face. Patients were excluded if they had a history of receiving PBBL treatment; had a history of scarring, hypopigmentation, or hyperpigmentation from laser or light treatments; and/or were pregnant or refused use of contraception during the study period.

Study Design

This single-blind, randomized, split-face study was approved by the institutional review board of the University of Pennsylvania (Philadelphia, Pennsylvania). All participants provided informed consent before entering the study. Each participant was randomly assigned to receive PBBL on one side of the face for 6 consecutive weeks and apply adapalene gel 0.3% to both sides of the face nightly for 10 weeks. Pneumatic broadband light treatment was performed using the following settings: starting power 2 (approximately 4–6 J/cm²) and vacuum setting 3 (negative pressure, approximately 3 lb/in²). The power setting was increased to a maximum of 6 (12–14 J/cm²) at subsequent visits depending on tolerability of the participants.

All participants visited the clinic weekly for 6 weeks and also returned for follow-up at week 10 (4 weeks following last PBBL treatment). At each visit, the participants completed satisfaction questionnaires and were assessed by a dermatologist evaluator using several parameters including the modified Global Acne Grading Score (mGAGS), clinical photography, participant self-assessment, physician assessment, and Wong Baker FACES Pain Rating Scale (WBPRS). The physician evaluator was blinded to the side of the face receiving PBBL treatment. Clinical photographs were taken to compare the clinical outcome at each visit versus baseline.

Efficacy Evaluation

Acne Counts

The blinded evaluator counted acne lesions and assessed the mGAGS at each visit prior to administration of the PBBL treatment. Acne lesions were counted separately as noninflammatory (comedones) and inflammatory (papules, pustules, nodules) on the forehead, cheeks, nose, and chin.

Modified Global Acne Grading Score

The modified Global Acne Grading Score was modified from the Global Acne Grading Scale (GAGS) that has previously been used to evaluate acne severity.⁵ The original GAGS used the type and location of the acne lesions. The GAGS considers 6 locations on the face, chest, and upper back, with a grading factor for each location (forehead=2; cheeks=2; nose=1; chin=1). Another grading factor represented the lesion type (0=no lesion; 1=comedone; 2=papule; 3=pustule; 4=nodule). The local score was calculated by multiplying the location grading factor by the lesion type grading factor. The total score was the sum of the individual local scores for the 4 locations.

Given that the number of acne lesions is important, we modified the GAGS by adding a grading factor that represented the number of lesions to improve the accuracy of the test (1=0–10 lesions; 2=11–20 lesions; 3=21–30 lesions; 4=≥31 lesions). The local score of mGAGS was calculated by multiplying the grading factors for location, lesion type, and number of lesions. Each local score was then added to yield a total score. The mGAGS may be useful and more accurate to determine the severity of acne (0=none; 1–44=mild; 45–80=moderate; 81–132=severe; 133–176=very severe).

Participant Self-assessment

Participants assessed their acne lesions using an 11-point rating scale (–5=100% worsening; –4=76%–99% worsening; –3=51%–75% worsening; –2=26%–50% worsening; –1=1%–25% worsening; 0=no improvement; 1=1%–25% improvement; 2=26%–50% improvement; 3=51%–75% improvement; 4=76%–99% improvement; 5=100% acne clear) to compare their acne at each treatment visit and week 10 follow-up with a baseline photograph.

Physician Assessment

The blinded evaluator assessed acne lesions on the face using the same 11-point rating scale that was used for participant self-assessment. For each participant, assessments were made at each treatment visit and week 10 follow-up by comparing baseline photographs.

Safety Evaluation

The WBPRS score, a standardized 6-point scale (0=no pain; 1=hurts a little bit; 2=hurts a little bit more; 3=hurts even more; 4=hurts whole lot; 5=hurt worst),⁶ was used to evaluate pain toleration during PBBL treatments and was recorded along with adverse events throughout the study.

Statistical Analysis

Based on data from 2 prior studies,3,7 we expected that the favorable clinical outcome of adapalene gel 0.3% and PBBL therapy would be 23% and 78%, respectively. If the adjunctive therapy with PBBL was beneficial, the favorable outcome would be higher than 78%. To be able to detect this difference, the sample size of 11 patients was needed when 5% type I error and 20% type II error were accepted.

Categorical variables were expressed as percentages, while continuous variables were expressed in terms of median (range). The clinical outcomes between both treatment groups were compared using the Wilcoxon signed rank test. A 2-tailed P value of ≤.05 was considered statistically significant. All statistical calculations were performed using STATA software version 10.0.

RESULTS
Baseline Characteristics

Four male and 7 female patients aged 18 to 35 years (median, 23 years) with mild to moderate acne were enrolled in the study. Of the 11 participants, 7 were white, 2 were black, 1 was Asian, and 1 was Latin American. Baseline characteristics of both sides of the face were comparable in all participants (Table 1). Eight participants (73%) completed the study. Two black participants withdrew from the study due to hyperpigmentation following PBBL treatment; 1 participant did not return for follow-up at week 10, as she was out of the country.

Lesion Counts

At week 3, reduction in noninflammatory lesions was significantly greater on the side receiving the combination therapy compared to the monotherapy side (P=.04)(Table 2). However, there was no significant difference between the combination therapy and the adapalene monotherapy sides in the reduction of noninflammatory and inflammatory lesions at week 4 (Figure 1). There was a remarkable improvement of the combination therapy and adapalene monotherapy sides in acne lesions, but there was no significant difference between the combination therapy and the adapalene monotherapy sides (Figure 2).

Modified Global Acne Grading Score

At weeks 3 and 4, the improvement of mGAGS was significantly greater on the side treated with the combination therapy (P=.05). However, this significant difference was not sustained (Table 3).

Participant Self-assessment and Physician Assessment

The rate of acne improvement according to participant self-assessment was slightly higher on the side receiving the combination therapy compared to the monotherapy side at week 2 (26%–50% vs 1%–25%) and week 6 (76%–99% vs 51%–75%). However, there was no statistically significant difference. For the physician assessment, there was no significant difference between the monotherapy and combination therapy sides.

Safety

The median WBPRS score was 1 (hurts a little bit) throughout all PBBL treatment visits. The maximum score was highest at week 1 (4=hurts whole lot) and subsequently decreased to 2 (hurts a little bit more) at week 6.

After the PBBL treatment, all participants experienced transient erythema in the treatment area. All participants noted their skin had become drier than usual from adapalene, except 1 participant (11%) who reported very dry skin on areas where adapalene gel 0.3% had been applied. However, the dryness was tolerable and relief was reported following application of a moisturizer. No participants withdrew from the study due to skin dryness.

Both black participants experienced hyperpigmentation caused by PBBL (1 on the treatment sites, the other on the test spot) and withdrew from the study. The hyperpigmentation resolved over time following application of a topical bleaching cream. One patient experienced purpura following PBBL treatment at week 4, which was associated with an increase in PBBL power. No other side effects (eg, scaling, stinging, burning, vesicle formation, blistering, crusting, scarring) were observed.

COMMENT

This 10-week study demonstrated that PBBL initially improved the appearance of acne in the first month of treatment, as determined by the significantly greater reduction in mGAGS for the combination side versus the adapalene monotherapy side. Differences in the reduction of acne lesions were not significant between the 2 treatments, except for noninflammatory lesion reduction at week 3. Analysis of physician assessment with photographs revealed acne improvement from baseline in the first month but no additional effects with the PBBL treatment at the end of study. Similarly, participant assessment indicated an improvement by week 2 with the combination therapy compared to adapalene monotherapy in their assessment of acne lesion reductions from baseline. By the end of the study, there was no significant difference between monotherapy and combination therapy.

These findings illustrate that combination therapy with PBBL plus adapalene improved the appearance of acne lesions within the first month of treatment, but there were no further signs of improvement at weeks 5 and 6. These results are consistent with at least 2 other studies that demonstrated acne reduction within the first 3 weeks of PBBL treatment.^2,4 The current study was completed as planned with 6 weeks of combination therapy and patients continued adapalene application until the last follow-up visit in week 10. The length of the combination treatment was enough to determine that extension of treatment would not be necessary to gain any further benefits in this study. Because of the small sample size, we would not be able to detect any significant differences, as the difference between the combination therapy and the adapalene monotherapy was less than 55%. Therefore, a future study with a larger sample size is needed to draw a better conclusion.

Pneumatic broadband light has shown impressive results in acne treatment. However, some side effects need to be considered. Minimal adverse events have been reported such as erythema, dryness, peeling, burning, and itching.^2-4 In this study, we found that all patients experienced transient erythema during and after PBBL treatment, but this effect disappeared in minutes. Purpura can occur if a higher power of PBBL is performed (6 or greater). Black patients experienced hyperpigmentation that can occur in darker skin types, as reported when light therapy is performed despite using the correct skin type tips.⁸ Therefore, care must be used in darker skin types, and we advocate a skin test in this population prior to general use.

Our study showed that PBBL can be safely combined with adapalene gel 0.3% and is well tolerated in the treatment of mild to moderate facial acne vulgaris for patients with Fitzpatrick skin types I to III. The combination of PBBL and adapalene reduces acne severity, as shown by the reduction in mGAGS during the first month of treatment. Patients noted faster improvement in their acne lesions with this combination. Although this study was limited by a relatively small sample size, this information may be useful in getting patients to be compliant overall, as they appeared to see results sooner, giving other therapies time to initiate their effect. It appears that 4 consecutive weekly treatments are enough to see that effect. Additionally, this combination therapy provides results without having to resort to oral antibiotics, as many patients today are concerned about creating future antibiotic resistance.

Conclusion

Adapalene gel 0.3% can be safely combined with PBBL for treatment of mild to moderate acne. Although the benefits of this combination therapy can be seen after 4 consecutive weekly treatments, the beneficial effect is not sustained.

Acknowledgment

The authors would like to thank Joyce Okawa, RN (Philadelphia, Pennsylvania), for her assistance in the submission to the University of Pennsylvania institutional review board.

Acne is a common and distressing condition that typically presents in adolescents and young adults and has been associated with not only medical but also emotional and aesthetic consequences. Acne treatments that offer faster improvement are the coveted goal. Although clinical studies support the use of combination therapy with topical retinoids and antibiotics, the overuse of antibiotics raises caution for bacterial resistance.1 Therefore, adjunctive treatments such as chemical peels, light therapy, and laser treatments can hasten the response to traditional acne treatments and in some cases may potentially decrease use of both oral and topical antibiotics.

Light therapy, particularly with visible light, may improve acne outcomes. Pneumatic broadband light (PBBL) is a light treatment in the broadband range (400–1200 nm) combined with a vacuum. The suction created by the vacuum has several effects on acne lesions, such as creating a mechanical lysis of thin-walled pustules and dislodging pore impaction. The blue light with a wavelength of 410 nm targets endogenous porphyrins in Propionibacterium acnes and elicits singlet oxygen production, resulting in bacterial destruction.^2,3 Studies showed that PBBL alone was effective in most patients with mild to moderate acne and caused minimal side effects.^2-4

We sought to determine if PBBL combined with a topical retinoid can accelerate and prolong acne improvement. We evaluated the efficacy, safety, and tolerability of PBBL plus adapalene gel 0.3% versus adapalene gel 0.3% monotherapy in patients with mild to moderate acne.

METHODSPatient Population

Patients with mild to moderate acne were eligible for the study if they were 18 years or older at screening, in good health, had stopped oral isotretinoin for at least 1 year prior to treatment initiation, and were not taking oral or topical antibiotics or using any topical retinoid derivatives for at least 1 month prior to treatment initiation. Inclusion criteria included at least 10 acne lesions on the face. Patients were excluded if they had a history of receiving PBBL treatment; had a history of scarring, hypopigmentation, or hyperpigmentation from laser or light treatments; and/or were pregnant or refused use of contraception during the study period.

Study Design

This single-blind, randomized, split-face study was approved by the institutional review board of the University of Pennsylvania (Philadelphia, Pennsylvania). All participants provided informed consent before entering the study. Each participant was randomly assigned to receive PBBL on one side of the face for 6 consecutive weeks and apply adapalene gel 0.3% to both sides of the face nightly for 10 weeks. Pneumatic broadband light treatment was performed using the following settings: starting power 2 (approximately 4–6 J/cm²) and vacuum setting 3 (negative pressure, approximately 3 lb/in²). The power setting was increased to a maximum of 6 (12–14 J/cm²) at subsequent visits depending on tolerability of the participants.

All participants visited the clinic weekly for 6 weeks and also returned for follow-up at week 10 (4 weeks following last PBBL treatment). At each visit, the participants completed satisfaction questionnaires and were assessed by a dermatologist evaluator using several parameters including the modified Global Acne Grading Score (mGAGS), clinical photography, participant self-assessment, physician assessment, and Wong Baker FACES Pain Rating Scale (WBPRS). The physician evaluator was blinded to the side of the face receiving PBBL treatment. Clinical photographs were taken to compare the clinical outcome at each visit versus baseline.

Efficacy Evaluation

Acne Counts

The blinded evaluator counted acne lesions and assessed the mGAGS at each visit prior to administration of the PBBL treatment. Acne lesions were counted separately as noninflammatory (comedones) and inflammatory (papules, pustules, nodules) on the forehead, cheeks, nose, and chin.

Modified Global Acne Grading Score

The modified Global Acne Grading Score was modified from the Global Acne Grading Scale (GAGS) that has previously been used to evaluate acne severity.⁵ The original GAGS used the type and location of the acne lesions. The GAGS considers 6 locations on the face, chest, and upper back, with a grading factor for each location (forehead=2; cheeks=2; nose=1; chin=1). Another grading factor represented the lesion type (0=no lesion; 1=comedone; 2=papule; 3=pustule; 4=nodule). The local score was calculated by multiplying the location grading factor by the lesion type grading factor. The total score was the sum of the individual local scores for the 4 locations.

Given that the number of acne lesions is important, we modified the GAGS by adding a grading factor that represented the number of lesions to improve the accuracy of the test (1=0–10 lesions; 2=11–20 lesions; 3=21–30 lesions; 4=≥31 lesions). The local score of mGAGS was calculated by multiplying the grading factors for location, lesion type, and number of lesions. Each local score was then added to yield a total score. The mGAGS may be useful and more accurate to determine the severity of acne (0=none; 1–44=mild; 45–80=moderate; 81–132=severe; 133–176=very severe).

Participant Self-assessment

Participants assessed their acne lesions using an 11-point rating scale (–5=100% worsening; –4=76%–99% worsening; –3=51%–75% worsening; –2=26%–50% worsening; –1=1%–25% worsening; 0=no improvement; 1=1%–25% improvement; 2=26%–50% improvement; 3=51%–75% improvement; 4=76%–99% improvement; 5=100% acne clear) to compare their acne at each treatment visit and week 10 follow-up with a baseline photograph.

Physician Assessment

The blinded evaluator assessed acne lesions on the face using the same 11-point rating scale that was used for participant self-assessment. For each participant, assessments were made at each treatment visit and week 10 follow-up by comparing baseline photographs.

Safety Evaluation

The WBPRS score, a standardized 6-point scale (0=no pain; 1=hurts a little bit; 2=hurts a little bit more; 3=hurts even more; 4=hurts whole lot; 5=hurt worst),⁶ was used to evaluate pain toleration during PBBL treatments and was recorded along with adverse events throughout the study.

Statistical Analysis

Based on data from 2 prior studies,3,7 we expected that the favorable clinical outcome of adapalene gel 0.3% and PBBL therapy would be 23% and 78%, respectively. If the adjunctive therapy with PBBL was beneficial, the favorable outcome would be higher than 78%. To be able to detect this difference, the sample size of 11 patients was needed when 5% type I error and 20% type II error were accepted.

Categorical variables were expressed as percentages, while continuous variables were expressed in terms of median (range). The clinical outcomes between both treatment groups were compared using the Wilcoxon signed rank test. A 2-tailed P value of ≤.05 was considered statistically significant. All statistical calculations were performed using STATA software version 10.0.

RESULTS
Baseline Characteristics

Four male and 7 female patients aged 18 to 35 years (median, 23 years) with mild to moderate acne were enrolled in the study. Of the 11 participants, 7 were white, 2 were black, 1 was Asian, and 1 was Latin American. Baseline characteristics of both sides of the face were comparable in all participants (Table 1). Eight participants (73%) completed the study. Two black participants withdrew from the study due to hyperpigmentation following PBBL treatment; 1 participant did not return for follow-up at week 10, as she was out of the country.

Lesion Counts

At week 3, reduction in noninflammatory lesions was significantly greater on the side receiving the combination therapy compared to the monotherapy side (P=.04)(Table 2). However, there was no significant difference between the combination therapy and the adapalene monotherapy sides in the reduction of noninflammatory and inflammatory lesions at week 4 (Figure 1). There was a remarkable improvement of the combination therapy and adapalene monotherapy sides in acne lesions, but there was no significant difference between the combination therapy and the adapalene monotherapy sides (Figure 2).

Modified Global Acne Grading Score

At weeks 3 and 4, the improvement of mGAGS was significantly greater on the side treated with the combination therapy (P=.05). However, this significant difference was not sustained (Table 3).

Participant Self-assessment and Physician Assessment

The rate of acne improvement according to participant self-assessment was slightly higher on the side receiving the combination therapy compared to the monotherapy side at week 2 (26%–50% vs 1%–25%) and week 6 (76%–99% vs 51%–75%). However, there was no statistically significant difference. For the physician assessment, there was no significant difference between the monotherapy and combination therapy sides.

Safety

The median WBPRS score was 1 (hurts a little bit) throughout all PBBL treatment visits. The maximum score was highest at week 1 (4=hurts whole lot) and subsequently decreased to 2 (hurts a little bit more) at week 6.

After the PBBL treatment, all participants experienced transient erythema in the treatment area. All participants noted their skin had become drier than usual from adapalene, except 1 participant (11%) who reported very dry skin on areas where adapalene gel 0.3% had been applied. However, the dryness was tolerable and relief was reported following application of a moisturizer. No participants withdrew from the study due to skin dryness.

Both black participants experienced hyperpigmentation caused by PBBL (1 on the treatment sites, the other on the test spot) and withdrew from the study. The hyperpigmentation resolved over time following application of a topical bleaching cream. One patient experienced purpura following PBBL treatment at week 4, which was associated with an increase in PBBL power. No other side effects (eg, scaling, stinging, burning, vesicle formation, blistering, crusting, scarring) were observed.

COMMENT

This 10-week study demonstrated that PBBL initially improved the appearance of acne in the first month of treatment, as determined by the significantly greater reduction in mGAGS for the combination side versus the adapalene monotherapy side. Differences in the reduction of acne lesions were not significant between the 2 treatments, except for noninflammatory lesion reduction at week 3. Analysis of physician assessment with photographs revealed acne improvement from baseline in the first month but no additional effects with the PBBL treatment at the end of study. Similarly, participant assessment indicated an improvement by week 2 with the combination therapy compared to adapalene monotherapy in their assessment of acne lesion reductions from baseline. By the end of the study, there was no significant difference between monotherapy and combination therapy.

These findings illustrate that combination therapy with PBBL plus adapalene improved the appearance of acne lesions within the first month of treatment, but there were no further signs of improvement at weeks 5 and 6. These results are consistent with at least 2 other studies that demonstrated acne reduction within the first 3 weeks of PBBL treatment.^2,4 The current study was completed as planned with 6 weeks of combination therapy and patients continued adapalene application until the last follow-up visit in week 10. The length of the combination treatment was enough to determine that extension of treatment would not be necessary to gain any further benefits in this study. Because of the small sample size, we would not be able to detect any significant differences, as the difference between the combination therapy and the adapalene monotherapy was less than 55%. Therefore, a future study with a larger sample size is needed to draw a better conclusion.

Pneumatic broadband light has shown impressive results in acne treatment. However, some side effects need to be considered. Minimal adverse events have been reported such as erythema, dryness, peeling, burning, and itching.^2-4 In this study, we found that all patients experienced transient erythema during and after PBBL treatment, but this effect disappeared in minutes. Purpura can occur if a higher power of PBBL is performed (6 or greater). Black patients experienced hyperpigmentation that can occur in darker skin types, as reported when light therapy is performed despite using the correct skin type tips.⁸ Therefore, care must be used in darker skin types, and we advocate a skin test in this population prior to general use.

Our study showed that PBBL can be safely combined with adapalene gel 0.3% and is well tolerated in the treatment of mild to moderate facial acne vulgaris for patients with Fitzpatrick skin types I to III. The combination of PBBL and adapalene reduces acne severity, as shown by the reduction in mGAGS during the first month of treatment. Patients noted faster improvement in their acne lesions with this combination. Although this study was limited by a relatively small sample size, this information may be useful in getting patients to be compliant overall, as they appeared to see results sooner, giving other therapies time to initiate their effect. It appears that 4 consecutive weekly treatments are enough to see that effect. Additionally, this combination therapy provides results without having to resort to oral antibiotics, as many patients today are concerned about creating future antibiotic resistance.

Conclusion

Adapalene gel 0.3% can be safely combined with PBBL for treatment of mild to moderate acne. Although the benefits of this combination therapy can be seen after 4 consecutive weekly treatments, the beneficial effect is not sustained.

Acknowledgment

The authors would like to thank Joyce Okawa, RN (Philadelphia, Pennsylvania), for her assistance in the submission to the University of Pennsylvania institutional review board.

Over the past few years there have been studies published that support a relationship between acne and nutritional factors. Most suggest that high-glycemic-load diets and milk/dairy consumption might promote the development or exacerbation of acne vulgaris. So, what’s the mechanism? Some investigators believe that a high-glycemic-index diet induces hyperinsulinemia, which in turn elicits endocrine responses such as increasing androgen synthesis, ultimately inducing acne through mediators such as androgens, insulinlike growth factor (IGF) 1, and IGF binding protein 3. Insulinlike growth factor 1 itself can induce keratinocyte proliferation, sebocyte proliferation, and sebum production. We know that acne can be related to some endocrine diseases, such as polycystic ovary syndrome, which is characterized by peripheral insulin resistance and hyperinsulinemia, as well as acne, hirsutism, and androgenic alopecia.

In a study published by Çerman et al (J Am Acad Dermatol. 2016;75:155-162), investigators aimed to support the relationship between acne and diet and proposed that adiponectin levels, an adipocyte-derived hormone with established anti-inflammatory, antioxidant, and antidiabetic effects, are inversely associated with glycemic intake. Adiponectin inhibits proinflammatory cytokines, downregulates adhesion molecule expression, suppresses toll-like receptors and their ligands, and increases insulin sensitivity. In this small study of 50 patients with acne matched to 36 healthy controls, mean (SD) serum adiponectin concentrations were significantly lower in the patients with acne vulgaris than in the healthy controls (9.93 [2.29] ng/mL^_1 vs 11.28 [2.74] ng/mL^_1; P=.015), though milk and dairy product consumption, serum glucose, insulin, IGF-1, IGF binding protein 3, and homeostasis model assessment of insulin resistance values of the acne vulgaris and control groups did not differ significantly. The authors argued that this finding supports low-glycemic-load diets given the inverse correlation with adiponectin concentrations.

For every promising study comes one that may refute it. A study published online in February 2016 in Human & Experimental Toxicology aimed to evaluate several adipokines (adipocyte-derived cytokines) such as leptin, adiponectin, ghrelin and adiponectin levels, and adiponectin and leptin rates that indicate insulin resistance in nonobese patients with severe acne vulgaris. Although this study was smaller (30 acne patients and 15 controls), investigators found no difference between the 2 groups for any of these adipokines. It is important to note that patients studied were nonobese, nondiabetic, and glycemic load was not taken into account, so it is possible that this correlation is more significant for patients with factors such as insulin resistance and obesity.

What’s the issue?

Regardless of these findings, we have enough evidence to support that eating poorly can worsen acne and have other effects on the body. Are we all in agreement with this conclusion? Eating poorly is bad for more than just acne. High glycemic load leads to a proinflammatory state. Think psoriasis here. Chronic inflammation is detrimental for every organ system. Therefore, in addition to focusing on the pathways and elucidating the biology, let’s also design curricula to train current and future dermatologists how to counsel patients on diet or at the very least create resources to enable us to guide our patients. I published a survey study (J Am Acad Dermatol. 2014;71:1028-1029) showing that dermatologists are not comfortable counseling patients, specifically psoriasis patients, on diet, smoking, and drinking alcohol. It is time to create these tools. Do you want these types of resources?

We want to know your views! Tell us what you think.

Over the past few years there have been studies published that support a relationship between acne and nutritional factors. Most suggest that high-glycemic-load diets and milk/dairy consumption might promote the development or exacerbation of acne vulgaris. So, what’s the mechanism? Some investigators believe that a high-glycemic-index diet induces hyperinsulinemia, which in turn elicits endocrine responses such as increasing androgen synthesis, ultimately inducing acne through mediators such as androgens, insulinlike growth factor (IGF) 1, and IGF binding protein 3. Insulinlike growth factor 1 itself can induce keratinocyte proliferation, sebocyte proliferation, and sebum production. We know that acne can be related to some endocrine diseases, such as polycystic ovary syndrome, which is characterized by peripheral insulin resistance and hyperinsulinemia, as well as acne, hirsutism, and androgenic alopecia.

In a study published by Çerman et al (J Am Acad Dermatol. 2016;75:155-162), investigators aimed to support the relationship between acne and diet and proposed that adiponectin levels, an adipocyte-derived hormone with established anti-inflammatory, antioxidant, and antidiabetic effects, are inversely associated with glycemic intake. Adiponectin inhibits proinflammatory cytokines, downregulates adhesion molecule expression, suppresses toll-like receptors and their ligands, and increases insulin sensitivity. In this small study of 50 patients with acne matched to 36 healthy controls, mean (SD) serum adiponectin concentrations were significantly lower in the patients with acne vulgaris than in the healthy controls (9.93 [2.29] ng/mL^_1 vs 11.28 [2.74] ng/mL^_1; P=.015), though milk and dairy product consumption, serum glucose, insulin, IGF-1, IGF binding protein 3, and homeostasis model assessment of insulin resistance values of the acne vulgaris and control groups did not differ significantly. The authors argued that this finding supports low-glycemic-load diets given the inverse correlation with adiponectin concentrations.

For every promising study comes one that may refute it. A study published online in February 2016 in Human & Experimental Toxicology aimed to evaluate several adipokines (adipocyte-derived cytokines) such as leptin, adiponectin, ghrelin and adiponectin levels, and adiponectin and leptin rates that indicate insulin resistance in nonobese patients with severe acne vulgaris. Although this study was smaller (30 acne patients and 15 controls), investigators found no difference between the 2 groups for any of these adipokines. It is important to note that patients studied were nonobese, nondiabetic, and glycemic load was not taken into account, so it is possible that this correlation is more significant for patients with factors such as insulin resistance and obesity.

What’s the issue?

Regardless of these findings, we have enough evidence to support that eating poorly can worsen acne and have other effects on the body. Are we all in agreement with this conclusion? Eating poorly is bad for more than just acne. High glycemic load leads to a proinflammatory state. Think psoriasis here. Chronic inflammation is detrimental for every organ system. Therefore, in addition to focusing on the pathways and elucidating the biology, let’s also design curricula to train current and future dermatologists how to counsel patients on diet or at the very least create resources to enable us to guide our patients. I published a survey study (J Am Acad Dermatol. 2014;71:1028-1029) showing that dermatologists are not comfortable counseling patients, specifically psoriasis patients, on diet, smoking, and drinking alcohol. It is time to create these tools. Do you want these types of resources?

We want to know your views! Tell us what you think.

Over the past few years there have been studies published that support a relationship between acne and nutritional factors. Most suggest that high-glycemic-load diets and milk/dairy consumption might promote the development or exacerbation of acne vulgaris. So, what’s the mechanism? Some investigators believe that a high-glycemic-index diet induces hyperinsulinemia, which in turn elicits endocrine responses such as increasing androgen synthesis, ultimately inducing acne through mediators such as androgens, insulinlike growth factor (IGF) 1, and IGF binding protein 3. Insulinlike growth factor 1 itself can induce keratinocyte proliferation, sebocyte proliferation, and sebum production. We know that acne can be related to some endocrine diseases, such as polycystic ovary syndrome, which is characterized by peripheral insulin resistance and hyperinsulinemia, as well as acne, hirsutism, and androgenic alopecia.

In a study published by Çerman et al (J Am Acad Dermatol. 2016;75:155-162), investigators aimed to support the relationship between acne and diet and proposed that adiponectin levels, an adipocyte-derived hormone with established anti-inflammatory, antioxidant, and antidiabetic effects, are inversely associated with glycemic intake. Adiponectin inhibits proinflammatory cytokines, downregulates adhesion molecule expression, suppresses toll-like receptors and their ligands, and increases insulin sensitivity. In this small study of 50 patients with acne matched to 36 healthy controls, mean (SD) serum adiponectin concentrations were significantly lower in the patients with acne vulgaris than in the healthy controls (9.93 [2.29] ng/mL^_1 vs 11.28 [2.74] ng/mL^_1; P=.015), though milk and dairy product consumption, serum glucose, insulin, IGF-1, IGF binding protein 3, and homeostasis model assessment of insulin resistance values of the acne vulgaris and control groups did not differ significantly. The authors argued that this finding supports low-glycemic-load diets given the inverse correlation with adiponectin concentrations.

For every promising study comes one that may refute it. A study published online in February 2016 in Human & Experimental Toxicology aimed to evaluate several adipokines (adipocyte-derived cytokines) such as leptin, adiponectin, ghrelin and adiponectin levels, and adiponectin and leptin rates that indicate insulin resistance in nonobese patients with severe acne vulgaris. Although this study was smaller (30 acne patients and 15 controls), investigators found no difference between the 2 groups for any of these adipokines. It is important to note that patients studied were nonobese, nondiabetic, and glycemic load was not taken into account, so it is possible that this correlation is more significant for patients with factors such as insulin resistance and obesity.

What’s the issue?

Regardless of these findings, we have enough evidence to support that eating poorly can worsen acne and have other effects on the body. Are we all in agreement with this conclusion? Eating poorly is bad for more than just acne. High glycemic load leads to a proinflammatory state. Think psoriasis here. Chronic inflammation is detrimental for every organ system. Therefore, in addition to focusing on the pathways and elucidating the biology, let’s also design curricula to train current and future dermatologists how to counsel patients on diet or at the very least create resources to enable us to guide our patients. I published a survey study (J Am Acad Dermatol. 2014;71:1028-1029) showing that dermatologists are not comfortable counseling patients, specifically psoriasis patients, on diet, smoking, and drinking alcohol. It is time to create these tools. Do you want these types of resources?

We want to know your views! Tell us what you think.

While euthanasia and physician-assisted suicide increasingly are being legalized around the world, there appears to be little evidence that vulnerable patients are being targeted by abuse of the practice, researchers say.

A review published in the July 5 edition of JAMA examined surveys and death certification studies from countries and jurisdictions where physician-assisted suicide, euthanasia or both have been legalized, to explore attitudes and practices.

©aga7ta/Thinkstock

Currently, physician-assisted suicide is legal in five U.S. states – California, Montana, Oregon, Vermont, and Washington – while euthanasia or physician-assisted suicide is legal in Belgium, Canada, Colombia, Luxembourg, the Netherlands, and Switzerland, (JAMA 2016;316:79-90. doi: 10.1001/jama.2016.8499).

The review found evidence suggesting that in the United States, physician-assisted suicide accounts for less than 0.4% of all deaths. In Belgium and the Netherlands, that prevalence is much higher; the most recent studies suggested that 4.6% of all deaths in Belgium and 2.9% of all deaths in the Netherlands can be attributed to euthanasia or physician-assisted suicide, and there is the suggestion that this proportion is increasing over time.

The authors also addressed the so-called “slippery slope” argument, which posits that legalization of euthanasia or physician-assisted suicide would see its expansion to include patients who had not explicitly requested it. They noted that the incidence of deaths resulting from administration of lethal drugs without explicit patient consent appeared to have declined from 0.8% of deaths in the Netherlands in 1990 to 0.2% of deaths in 2010.

Similarly in Belgium, these deaths without explicit patient consent were estimated to be around 3.2% of deaths before legalization and 1.7% of deaths in 2013, after legalization.

“There is much debate concerning performing euthanasia, physician-assisted suicide, or other life-ending procedures on patients with dementia or chronic mental illness, who are minors, who are just “tired of life,” or who are socioeconomically vulnerable,” wrote Dr. Ezekiel J. Emanuel, vice provost for global initiatives and professor and chair of the department of medical ethics and health policy medical ethics and health policy at the University of Pennsylvania in Philadelphia, and coauthors.

However they cited a survey of Dutch physicians which found that only 2% of requests for euthanasia or physician-assisted suicide were from patients with a psychiatric disease, 4% were from patients with dementia, and 3% were from patients with neither a serious physical or psychiatric disease.

“In the United States, the concern that minorities, the disabled, the poor, or other socioeconomically marginalized groups might be pressured to accept [physician-assisted suicide] does not seem to be borne out,” the authors wrote. “The demographic profile of patients in the United States who have received these interventions is white, well-educated, and well-insured.”

The majority of cases of physician-assisted suicide or euthanasia in the Netherlands and Belgium – 70% – occur in patients with cancer, and 6% are among individuals with a neurodegenerative disease.

The authors also examined changing attitudes among the general public and among physicians towards physician-assisted suicide and euthanasia. They found that public support has declined slightly in the United States, from 75% in 2005 to 64% in 2012, but pointed out that assessing attitudes was challenging because of “framing effects” in surveys.

“Support varies substantially depending on the wording of survey questions; the provision of details about the patients, their prognosis, their medical diagnosis, and symptoms; how the interventions are characterized; and whether the questions are focused on ethical acceptability, legalization, or some other endorsement.”

Support for euthanasia and physician-assisted suicide has increased in most Western European nations but has either plateaued or decreased in much of Central and Eastern Europe.

“These changes seem correlated with a strong decline in religiosity in Western Europe and an increase in religiosity in post-communist Eastern Europe,” the authors suggested.

Physician surveys experience the same framing issues, but the authors cited a 2014 Medscape survey of physicians in seven countries which found that 54% of U.S. respondents agreed that physician-assisted suicide should be allowed, compared with 47% of respondents in Germany and the U.K., 42% in Italy, 30% in France, and 36% in Spain.

No conflicts of interest were reported.

While euthanasia and physician-assisted suicide increasingly are being legalized around the world, there appears to be little evidence that vulnerable patients are being targeted by abuse of the practice, researchers say.

A review published in the July 5 edition of JAMA examined surveys and death certification studies from countries and jurisdictions where physician-assisted suicide, euthanasia or both have been legalized, to explore attitudes and practices.

©aga7ta/Thinkstock

Currently, physician-assisted suicide is legal in five U.S. states – California, Montana, Oregon, Vermont, and Washington – while euthanasia or physician-assisted suicide is legal in Belgium, Canada, Colombia, Luxembourg, the Netherlands, and Switzerland, (JAMA 2016;316:79-90. doi: 10.1001/jama.2016.8499).

The review found evidence suggesting that in the United States, physician-assisted suicide accounts for less than 0.4% of all deaths. In Belgium and the Netherlands, that prevalence is much higher; the most recent studies suggested that 4.6% of all deaths in Belgium and 2.9% of all deaths in the Netherlands can be attributed to euthanasia or physician-assisted suicide, and there is the suggestion that this proportion is increasing over time.

The authors also addressed the so-called “slippery slope” argument, which posits that legalization of euthanasia or physician-assisted suicide would see its expansion to include patients who had not explicitly requested it. They noted that the incidence of deaths resulting from administration of lethal drugs without explicit patient consent appeared to have declined from 0.8% of deaths in the Netherlands in 1990 to 0.2% of deaths in 2010.

Similarly in Belgium, these deaths without explicit patient consent were estimated to be around 3.2% of deaths before legalization and 1.7% of deaths in 2013, after legalization.

“There is much debate concerning performing euthanasia, physician-assisted suicide, or other life-ending procedures on patients with dementia or chronic mental illness, who are minors, who are just “tired of life,” or who are socioeconomically vulnerable,” wrote Dr. Ezekiel J. Emanuel, vice provost for global initiatives and professor and chair of the department of medical ethics and health policy medical ethics and health policy at the University of Pennsylvania in Philadelphia, and coauthors.

However they cited a survey of Dutch physicians which found that only 2% of requests for euthanasia or physician-assisted suicide were from patients with a psychiatric disease, 4% were from patients with dementia, and 3% were from patients with neither a serious physical or psychiatric disease.

“In the United States, the concern that minorities, the disabled, the poor, or other socioeconomically marginalized groups might be pressured to accept [physician-assisted suicide] does not seem to be borne out,” the authors wrote. “The demographic profile of patients in the United States who have received these interventions is white, well-educated, and well-insured.”

The majority of cases of physician-assisted suicide or euthanasia in the Netherlands and Belgium – 70% – occur in patients with cancer, and 6% are among individuals with a neurodegenerative disease.

The authors also examined changing attitudes among the general public and among physicians towards physician-assisted suicide and euthanasia. They found that public support has declined slightly in the United States, from 75% in 2005 to 64% in 2012, but pointed out that assessing attitudes was challenging because of “framing effects” in surveys.

“Support varies substantially depending on the wording of survey questions; the provision of details about the patients, their prognosis, their medical diagnosis, and symptoms; how the interventions are characterized; and whether the questions are focused on ethical acceptability, legalization, or some other endorsement.”

Support for euthanasia and physician-assisted suicide has increased in most Western European nations but has either plateaued or decreased in much of Central and Eastern Europe.

“These changes seem correlated with a strong decline in religiosity in Western Europe and an increase in religiosity in post-communist Eastern Europe,” the authors suggested.

Physician surveys experience the same framing issues, but the authors cited a 2014 Medscape survey of physicians in seven countries which found that 54% of U.S. respondents agreed that physician-assisted suicide should be allowed, compared with 47% of respondents in Germany and the U.K., 42% in Italy, 30% in France, and 36% in Spain.

No conflicts of interest were reported.

While euthanasia and physician-assisted suicide increasingly are being legalized around the world, there appears to be little evidence that vulnerable patients are being targeted by abuse of the practice, researchers say.

A review published in the July 5 edition of JAMA examined surveys and death certification studies from countries and jurisdictions where physician-assisted suicide, euthanasia or both have been legalized, to explore attitudes and practices.

©aga7ta/Thinkstock

Currently, physician-assisted suicide is legal in five U.S. states – California, Montana, Oregon, Vermont, and Washington – while euthanasia or physician-assisted suicide is legal in Belgium, Canada, Colombia, Luxembourg, the Netherlands, and Switzerland, (JAMA 2016;316:79-90. doi: 10.1001/jama.2016.8499).

The review found evidence suggesting that in the United States, physician-assisted suicide accounts for less than 0.4% of all deaths. In Belgium and the Netherlands, that prevalence is much higher; the most recent studies suggested that 4.6% of all deaths in Belgium and 2.9% of all deaths in the Netherlands can be attributed to euthanasia or physician-assisted suicide, and there is the suggestion that this proportion is increasing over time.

The authors also addressed the so-called “slippery slope” argument, which posits that legalization of euthanasia or physician-assisted suicide would see its expansion to include patients who had not explicitly requested it. They noted that the incidence of deaths resulting from administration of lethal drugs without explicit patient consent appeared to have declined from 0.8% of deaths in the Netherlands in 1990 to 0.2% of deaths in 2010.

Similarly in Belgium, these deaths without explicit patient consent were estimated to be around 3.2% of deaths before legalization and 1.7% of deaths in 2013, after legalization.

“There is much debate concerning performing euthanasia, physician-assisted suicide, or other life-ending procedures on patients with dementia or chronic mental illness, who are minors, who are just “tired of life,” or who are socioeconomically vulnerable,” wrote Dr. Ezekiel J. Emanuel, vice provost for global initiatives and professor and chair of the department of medical ethics and health policy medical ethics and health policy at the University of Pennsylvania in Philadelphia, and coauthors.

However they cited a survey of Dutch physicians which found that only 2% of requests for euthanasia or physician-assisted suicide were from patients with a psychiatric disease, 4% were from patients with dementia, and 3% were from patients with neither a serious physical or psychiatric disease.

“In the United States, the concern that minorities, the disabled, the poor, or other socioeconomically marginalized groups might be pressured to accept [physician-assisted suicide] does not seem to be borne out,” the authors wrote. “The demographic profile of patients in the United States who have received these interventions is white, well-educated, and well-insured.”

The majority of cases of physician-assisted suicide or euthanasia in the Netherlands and Belgium – 70% – occur in patients with cancer, and 6% are among individuals with a neurodegenerative disease.

The authors also examined changing attitudes among the general public and among physicians towards physician-assisted suicide and euthanasia. They found that public support has declined slightly in the United States, from 75% in 2005 to 64% in 2012, but pointed out that assessing attitudes was challenging because of “framing effects” in surveys.

“Support varies substantially depending on the wording of survey questions; the provision of details about the patients, their prognosis, their medical diagnosis, and symptoms; how the interventions are characterized; and whether the questions are focused on ethical acceptability, legalization, or some other endorsement.”

Support for euthanasia and physician-assisted suicide has increased in most Western European nations but has either plateaued or decreased in much of Central and Eastern Europe.

“These changes seem correlated with a strong decline in religiosity in Western Europe and an increase in religiosity in post-communist Eastern Europe,” the authors suggested.

Physician surveys experience the same framing issues, but the authors cited a 2014 Medscape survey of physicians in seven countries which found that 54% of U.S. respondents agreed that physician-assisted suicide should be allowed, compared with 47% of respondents in Germany and the U.K., 42% in Italy, 30% in France, and 36% in Spain.

No conflicts of interest were reported.

Once-daily oral siponimod was associated with sustained effects on MRI outcomes at 24 months in patients with relapsing-remitting multiple sclerosis in a dose-blinded extension of the phase II study.

Disease activity was low, “with some evidence of greater benefit associated with siponimod at 10-mg, 2-mg, and 1.25-mg doses than with siponimod at 0.25-mg and 0.5-mg doses. No new safety signals emerged, and dose titration at treatment initiation mitigated cardiac effects,” Ludwig Kappos, MD, of University Hospital Basel (Switzerland), and his associates wrote in JAMA Neurology. “With similar efficacy but lower rates of lymphopenia relative to the 10-mg dose, siponimod 2 mg, has been chosen for further development,” they wrote.

Siponimod (BAF312) is a selective sphingosine 1-phosphate receptor (S1P_1,5) modulator that was evaluated for up to 6 months at five doses in the phase II BOLD (BAF312 on MRI Lesion Given Once Daily) study. Patients with relapsing-remitting MS who received 10 mg siponimod had up to 80% reductions in MRI combined unique active lesions (CUALs, or gadolinium-enhancing T1 lesions and/or new and newly enlarging T2 lesions, without double counting), compared with the placebo group. The 2-mg and 0.5-mg dose cohorts had reductions of 72% and 50%, respectively. The current study was a 24-month, dose-blinded extension phase that included 185 participants (73% of 252 eligible patients), of whom 33 patients received 10 mg siponimod, 29 received 2 mg, 43 received 1.25 mg, 29 received 0.5 mg, and 50 received 0.25 mg (JAMA Neurol. 2016 July 5. doi: 10.1001/jamaneurol.2016.1451).

Average reductions in gadolinium-enhancing T1 lesion counts were sustained in the 10-mg, 2-mg, 1.25-mg, and 0.5-mg dose groups at month 24, the researchers reported. The 1.25-mg and 2-mg doses yielded the highest proportions of patients free from new MRI activity (58% for both dose groups) and free from new or newly enlarging T2 lesions (61% and 58%, respectively). New or newly enlarging T2 lesions were numerically lower at doses exceeding 0.25 mg. “There were no clear changes in normalized brain volume within or between any of the treatment groups,” the investigators added.

Dose titration during the first 10 days of treatment mitigated bradycardia and atrioventricular conduction effects. Rates of adverse events within dose groups ranged from 84% to 97% and did not show a trend with dose size. Serious adverse events affected nine patients (5%) and included one case each of otosclerosis, gastritis, anaphylaxis, acute pyelonephritis, femoral and ankle fractures, basal cell carcinoma, cervical neoplasm, and abortion. Thirteen patients (7%) required treatment interruptions because of adverse events, of which seven consisted of lymphopenia or decreased lymphocyte count at the 10-mg dose. Other adverse events leading to dose interruptions or adjustments included neutropenia, upper respiratory tract infection, elevated hepatic transaminases, and hypertension.

Novartis is developing siponimod and funded the study. Coinvestigators employed by Novartis participated in all aspects of the study, including interpretation of the data and manuscript submission. Dr. Kappos disclosed financial ties to Novartis and numerous other pharmaceutical companies, foundations, and societies.

Once-daily oral siponimod was associated with sustained effects on MRI outcomes at 24 months in patients with relapsing-remitting multiple sclerosis in a dose-blinded extension of the phase II study.

Disease activity was low, “with some evidence of greater benefit associated with siponimod at 10-mg, 2-mg, and 1.25-mg doses than with siponimod at 0.25-mg and 0.5-mg doses. No new safety signals emerged, and dose titration at treatment initiation mitigated cardiac effects,” Ludwig Kappos, MD, of University Hospital Basel (Switzerland), and his associates wrote in JAMA Neurology. “With similar efficacy but lower rates of lymphopenia relative to the 10-mg dose, siponimod 2 mg, has been chosen for further development,” they wrote.

Siponimod (BAF312) is a selective sphingosine 1-phosphate receptor (S1P_1,5) modulator that was evaluated for up to 6 months at five doses in the phase II BOLD (BAF312 on MRI Lesion Given Once Daily) study. Patients with relapsing-remitting MS who received 10 mg siponimod had up to 80% reductions in MRI combined unique active lesions (CUALs, or gadolinium-enhancing T1 lesions and/or new and newly enlarging T2 lesions, without double counting), compared with the placebo group. The 2-mg and 0.5-mg dose cohorts had reductions of 72% and 50%, respectively. The current study was a 24-month, dose-blinded extension phase that included 185 participants (73% of 252 eligible patients), of whom 33 patients received 10 mg siponimod, 29 received 2 mg, 43 received 1.25 mg, 29 received 0.5 mg, and 50 received 0.25 mg (JAMA Neurol. 2016 July 5. doi: 10.1001/jamaneurol.2016.1451).

Average reductions in gadolinium-enhancing T1 lesion counts were sustained in the 10-mg, 2-mg, 1.25-mg, and 0.5-mg dose groups at month 24, the researchers reported. The 1.25-mg and 2-mg doses yielded the highest proportions of patients free from new MRI activity (58% for both dose groups) and free from new or newly enlarging T2 lesions (61% and 58%, respectively). New or newly enlarging T2 lesions were numerically lower at doses exceeding 0.25 mg. “There were no clear changes in normalized brain volume within or between any of the treatment groups,” the investigators added.

Dose titration during the first 10 days of treatment mitigated bradycardia and atrioventricular conduction effects. Rates of adverse events within dose groups ranged from 84% to 97% and did not show a trend with dose size. Serious adverse events affected nine patients (5%) and included one case each of otosclerosis, gastritis, anaphylaxis, acute pyelonephritis, femoral and ankle fractures, basal cell carcinoma, cervical neoplasm, and abortion. Thirteen patients (7%) required treatment interruptions because of adverse events, of which seven consisted of lymphopenia or decreased lymphocyte count at the 10-mg dose. Other adverse events leading to dose interruptions or adjustments included neutropenia, upper respiratory tract infection, elevated hepatic transaminases, and hypertension.

Novartis is developing siponimod and funded the study. Coinvestigators employed by Novartis participated in all aspects of the study, including interpretation of the data and manuscript submission. Dr. Kappos disclosed financial ties to Novartis and numerous other pharmaceutical companies, foundations, and societies.

Once-daily oral siponimod was associated with sustained effects on MRI outcomes at 24 months in patients with relapsing-remitting multiple sclerosis in a dose-blinded extension of the phase II study.

Disease activity was low, “with some evidence of greater benefit associated with siponimod at 10-mg, 2-mg, and 1.25-mg doses than with siponimod at 0.25-mg and 0.5-mg doses. No new safety signals emerged, and dose titration at treatment initiation mitigated cardiac effects,” Ludwig Kappos, MD, of University Hospital Basel (Switzerland), and his associates wrote in JAMA Neurology. “With similar efficacy but lower rates of lymphopenia relative to the 10-mg dose, siponimod 2 mg, has been chosen for further development,” they wrote.

Siponimod (BAF312) is a selective sphingosine 1-phosphate receptor (S1P_1,5) modulator that was evaluated for up to 6 months at five doses in the phase II BOLD (BAF312 on MRI Lesion Given Once Daily) study. Patients with relapsing-remitting MS who received 10 mg siponimod had up to 80% reductions in MRI combined unique active lesions (CUALs, or gadolinium-enhancing T1 lesions and/or new and newly enlarging T2 lesions, without double counting), compared with the placebo group. The 2-mg and 0.5-mg dose cohorts had reductions of 72% and 50%, respectively. The current study was a 24-month, dose-blinded extension phase that included 185 participants (73% of 252 eligible patients), of whom 33 patients received 10 mg siponimod, 29 received 2 mg, 43 received 1.25 mg, 29 received 0.5 mg, and 50 received 0.25 mg (JAMA Neurol. 2016 July 5. doi: 10.1001/jamaneurol.2016.1451).

Average reductions in gadolinium-enhancing T1 lesion counts were sustained in the 10-mg, 2-mg, 1.25-mg, and 0.5-mg dose groups at month 24, the researchers reported. The 1.25-mg and 2-mg doses yielded the highest proportions of patients free from new MRI activity (58% for both dose groups) and free from new or newly enlarging T2 lesions (61% and 58%, respectively). New or newly enlarging T2 lesions were numerically lower at doses exceeding 0.25 mg. “There were no clear changes in normalized brain volume within or between any of the treatment groups,” the investigators added.

Dose titration during the first 10 days of treatment mitigated bradycardia and atrioventricular conduction effects. Rates of adverse events within dose groups ranged from 84% to 97% and did not show a trend with dose size. Serious adverse events affected nine patients (5%) and included one case each of otosclerosis, gastritis, anaphylaxis, acute pyelonephritis, femoral and ankle fractures, basal cell carcinoma, cervical neoplasm, and abortion. Thirteen patients (7%) required treatment interruptions because of adverse events, of which seven consisted of lymphopenia or decreased lymphocyte count at the 10-mg dose. Other adverse events leading to dose interruptions or adjustments included neutropenia, upper respiratory tract infection, elevated hepatic transaminases, and hypertension.

Novartis is developing siponimod and funded the study. Coinvestigators employed by Novartis participated in all aspects of the study, including interpretation of the data and manuscript submission. Dr. Kappos disclosed financial ties to Novartis and numerous other pharmaceutical companies, foundations, and societies.

A deuterated form of the vesicular monoamine transporter type 2 inhibitor tetrabenazine, called deutetrabenazine, modestly reduced chorea of Huntington disease over 12 weeks in a phase III, double-blind, randomized, placebo-controlled trial.

First author Samuel Frank, MD, of Beth Israel Deaconess Medical Center in Boston and his colleagues in the Huntington Study Group wrote that the observed treatment effect of 2.5 points on the primary end point of total maximal chorea score, “taken together with improvements in patient-centered end points, such as PGIC [Patient Global Impression of Change] and SF-36 [36-Item Short Form] physical functioning component scales, may be of clinical relevance, although this remains to be determined. The difference in total maximal chorea score associated with deutetrabenazine treatment that was observed in this study is notable given the progressive decline in total maximal chorea score and total motor score that has been previously described as part of the natural history of Huntington disease.”

The phase III trial is the first to use an active ingredient with deuterium substituted for hydrogen at key positions. The use of deuterium in the molecule, according to the investigators, prolongs “plasma half-life and reduce[s] metabolic variability, without changing target pharmacology,” and its “longer half-life and unique pharmacokinetic profile ... may enable less frequent and lower daily doses, thus achieving similar systemic exposure with lower peak concentrations and simplified dosing, compared with tetrabenazine.”

Tetrabenazine (Xenazine) is used worldwide and is the only U.S. Food and Drug Administration–approved therapy for treating chorea associated with Huntington disease.

The trial enrolled 90 patients with genetically diagnosed Huntington disease across 34 centers in the United States and Canada. The patients had a baseline total maximal chorea score of 8 or higher (range 0-28) and were randomized on a 1:1 ratio to receive deuterated tetrabenazine (deutetrabenazine) or placebo. The deutetrabenazine group had a mean age of 55 years and 49% were male. The placebo group had a mean age of 52 years and 62% were men. Patients on the active drug were commenced at a total daily dose of 6 mg (divided into two doses) for the first week. Doses were then increased weekly by 6 mg daily until either chorea was adequately controlled or the maximum dose of 48 mg a day was reached. The final dose was maintained for an additional 4 weeks for a total of 12 weeks, followed by a 1-week washout (JAMA 2016;316[1]:40-50. doi: 10.1001/jama.2016.8655).

The total maximal chorea score, in which higher scores represent worse chorea, that was measured from baseline to an average across the maintenance period during weeks 9 through 12 of therapy declined by a statistically significant 4.4 points – from a mean of 12.1 to 7.7 – in the deutetrabenazine group, compared with a decline of 1.9 points – from a mean of 13.2 to 11.3 – in the placebo group.

Improvements in secondary endpoints such as PGIC and SF-36 physical functioning component scales were also seen in the treatment group, although no improvement was seen in the Berg Balance Test.

Adverse events were similar between the deutetrabenazine and placebo groups, including depression, anxiety, and akathisia.

“Further research is needed to assess the clinical importance of the effect size, and to determine longer-term efficacy and safety,” the study authors concluded.

The study was supported by Auspex Pharmaceuticals, a wholly owned subsidiary of Teva Pharmaceutical Industries. Dr. Frank reported receiving grants from the Huntington Study Group, and many other authors in the group reported financial ties to pharmaceutical companies, including Auspex and Teva. Several authors are employees of Auspex.

A deuterated form of the vesicular monoamine transporter type 2 inhibitor tetrabenazine, called deutetrabenazine, modestly reduced chorea of Huntington disease over 12 weeks in a phase III, double-blind, randomized, placebo-controlled trial.

First author Samuel Frank, MD, of Beth Israel Deaconess Medical Center in Boston and his colleagues in the Huntington Study Group wrote that the observed treatment effect of 2.5 points on the primary end point of total maximal chorea score, “taken together with improvements in patient-centered end points, such as PGIC [Patient Global Impression of Change] and SF-36 [36-Item Short Form] physical functioning component scales, may be of clinical relevance, although this remains to be determined. The difference in total maximal chorea score associated with deutetrabenazine treatment that was observed in this study is notable given the progressive decline in total maximal chorea score and total motor score that has been previously described as part of the natural history of Huntington disease.”

The phase III trial is the first to use an active ingredient with deuterium substituted for hydrogen at key positions. The use of deuterium in the molecule, according to the investigators, prolongs “plasma half-life and reduce[s] metabolic variability, without changing target pharmacology,” and its “longer half-life and unique pharmacokinetic profile ... may enable less frequent and lower daily doses, thus achieving similar systemic exposure with lower peak concentrations and simplified dosing, compared with tetrabenazine.”

Tetrabenazine (Xenazine) is used worldwide and is the only U.S. Food and Drug Administration–approved therapy for treating chorea associated with Huntington disease.

The trial enrolled 90 patients with genetically diagnosed Huntington disease across 34 centers in the United States and Canada. The patients had a baseline total maximal chorea score of 8 or higher (range 0-28) and were randomized on a 1:1 ratio to receive deuterated tetrabenazine (deutetrabenazine) or placebo. The deutetrabenazine group had a mean age of 55 years and 49% were male. The placebo group had a mean age of 52 years and 62% were men. Patients on the active drug were commenced at a total daily dose of 6 mg (divided into two doses) for the first week. Doses were then increased weekly by 6 mg daily until either chorea was adequately controlled or the maximum dose of 48 mg a day was reached. The final dose was maintained for an additional 4 weeks for a total of 12 weeks, followed by a 1-week washout (JAMA 2016;316[1]:40-50. doi: 10.1001/jama.2016.8655).

The total maximal chorea score, in which higher scores represent worse chorea, that was measured from baseline to an average across the maintenance period during weeks 9 through 12 of therapy declined by a statistically significant 4.4 points – from a mean of 12.1 to 7.7 – in the deutetrabenazine group, compared with a decline of 1.9 points – from a mean of 13.2 to 11.3 – in the placebo group.

Improvements in secondary endpoints such as PGIC and SF-36 physical functioning component scales were also seen in the treatment group, although no improvement was seen in the Berg Balance Test.

Adverse events were similar between the deutetrabenazine and placebo groups, including depression, anxiety, and akathisia.

“Further research is needed to assess the clinical importance of the effect size, and to determine longer-term efficacy and safety,” the study authors concluded.

The study was supported by Auspex Pharmaceuticals, a wholly owned subsidiary of Teva Pharmaceutical Industries. Dr. Frank reported receiving grants from the Huntington Study Group, and many other authors in the group reported financial ties to pharmaceutical companies, including Auspex and Teva. Several authors are employees of Auspex.

A deuterated form of the vesicular monoamine transporter type 2 inhibitor tetrabenazine, called deutetrabenazine, modestly reduced chorea of Huntington disease over 12 weeks in a phase III, double-blind, randomized, placebo-controlled trial.

First author Samuel Frank, MD, of Beth Israel Deaconess Medical Center in Boston and his colleagues in the Huntington Study Group wrote that the observed treatment effect of 2.5 points on the primary end point of total maximal chorea score, “taken together with improvements in patient-centered end points, such as PGIC [Patient Global Impression of Change] and SF-36 [36-Item Short Form] physical functioning component scales, may be of clinical relevance, although this remains to be determined. The difference in total maximal chorea score associated with deutetrabenazine treatment that was observed in this study is notable given the progressive decline in total maximal chorea score and total motor score that has been previously described as part of the natural history of Huntington disease.”

The phase III trial is the first to use an active ingredient with deuterium substituted for hydrogen at key positions. The use of deuterium in the molecule, according to the investigators, prolongs “plasma half-life and reduce[s] metabolic variability, without changing target pharmacology,” and its “longer half-life and unique pharmacokinetic profile ... may enable less frequent and lower daily doses, thus achieving similar systemic exposure with lower peak concentrations and simplified dosing, compared with tetrabenazine.”

Tetrabenazine (Xenazine) is used worldwide and is the only U.S. Food and Drug Administration–approved therapy for treating chorea associated with Huntington disease.

The trial enrolled 90 patients with genetically diagnosed Huntington disease across 34 centers in the United States and Canada. The patients had a baseline total maximal chorea score of 8 or higher (range 0-28) and were randomized on a 1:1 ratio to receive deuterated tetrabenazine (deutetrabenazine) or placebo. The deutetrabenazine group had a mean age of 55 years and 49% were male. The placebo group had a mean age of 52 years and 62% were men. Patients on the active drug were commenced at a total daily dose of 6 mg (divided into two doses) for the first week. Doses were then increased weekly by 6 mg daily until either chorea was adequately controlled or the maximum dose of 48 mg a day was reached. The final dose was maintained for an additional 4 weeks for a total of 12 weeks, followed by a 1-week washout (JAMA 2016;316[1]:40-50. doi: 10.1001/jama.2016.8655).

The total maximal chorea score, in which higher scores represent worse chorea, that was measured from baseline to an average across the maintenance period during weeks 9 through 12 of therapy declined by a statistically significant 4.4 points – from a mean of 12.1 to 7.7 – in the deutetrabenazine group, compared with a decline of 1.9 points – from a mean of 13.2 to 11.3 – in the placebo group.

Improvements in secondary endpoints such as PGIC and SF-36 physical functioning component scales were also seen in the treatment group, although no improvement was seen in the Berg Balance Test.

Adverse events were similar between the deutetrabenazine and placebo groups, including depression, anxiety, and akathisia.

“Further research is needed to assess the clinical importance of the effect size, and to determine longer-term efficacy and safety,” the study authors concluded.

The study was supported by Auspex Pharmaceuticals, a wholly owned subsidiary of Teva Pharmaceutical Industries. Dr. Frank reported receiving grants from the Huntington Study Group, and many other authors in the group reported financial ties to pharmaceutical companies, including Auspex and Teva. Several authors are employees of Auspex.

Lepromatous Leprosy

Lepromatous leprosy (LL) is a chronic, cutaneous, granulomatous infection caused by Mycobacterium leprae or the newly discovered Mycobacterium lepromatosis, both acid-fast, intracellular, bacillus bacterium.¹ Although decreasing in prevalence due to effective treatment with antimicrobials, LL continues to be endemic in warm tropical or subtropical areas in Southeast Asia, sub-Saharan Africa, the Indian subcontinent, and South America.¹ The mode of transmission of infection is not well established.

The cutaneous manifestation of leprosy was previously classified based on the cell-mediated immune response of the patient, as described by Ridley and Jopling,² ranging from tuberculoid leprosy (TT) to LL. In this spectrum of leprosy are the borderline lesions including borderline tuberculoid, borderline, and borderline lepromatous.^2,3 Although this classification is popular, in 2012 the World Health Organization implemented a new 2-category classification system to standardize treatment regimens: paucibacillary (2–5 lesions or 1 nerve involvement) and multibacillary (>5 lesions or multiple nerve involvement).⁴

In LL, a cell-mediated immune response is not mounted against the infection in the patient. Clinically, the disease can manifest as macular and nodular erythematous cutaneous lesions with poorly defined borders that are preferentially located on the face, earlobes, and nasal mucosa. Chronic infections are associated with sensory loss. Histologically, the dermis is densely infiltrated by foamy macrophages (Virchow cells or lepra cells), which do not form granulomas (quiz image A). The infiltrate may have varying accompanying lymphocytes and plasma cells, which can extend deep into the subcutaneous adipose tissue. Between the dermal infiltrate and epidermis is an uninvolved band of superficial dermis called the Grenz zone. The epidermis is flattened and atrophic. Nerves often are surrounded by macrophages with degrees of hyalinization but rarely are swollen. On acid-fast staining (Wade-Fite or Ziehl-Neelsen), numerous acid-fast bacilli are present within dermal cells in densely packed, intracellular collections called globi (quiz image B).^2,3,5

In TT, the robust immune response causes epithelioid granuloma formation, similar to cutaneous sarcoidosis, and few, if any, organisms can be found on special stains. The remaining borderline lesions have varying numbers of bacilli and varying amounts of granuloma formation.^3,6,7 Many cases of TT resolve without specific treatment. For most leprous diseases, the World Health Organization currently recommends a regimen of dapsone, rifampin, and clofazimine combination treatments for 6 to 12 months depending on the type of leprosy.⁸

Cutaneous leishmaniasis should be included in the differential diagnosis for patients from LL endemic areas. Early lesions can have a histiocytic infiltration with associated mixed inflammation and prominent epidermal hyperplasia. These early lesions usually have parasitic organisms located within the periphery of the cytoplasm of macrophages (“marquee sign”) to help differentiate it from leprous diseases (Figure 1).⁹

In nonendemic areas, leprous diseases often are mistaken for sarcoidosis, xanthomas, granular cell tumors, paraffinomas, or other histiocytic-rich lesions.¹⁰ Cutaneous sarcoidosis may be difficult to distinguish from TT, as both have noncaseating granulomas (Figure 2). Rare acid-fast bacilli may aid in the diagnosis, and sarcoid granulomas are not typically associated with cutaneous nerve involvement. New diagnostic tools such as polymerase chain reaction or genome sequencing can pick up rare organisms.

Xanthogranuolomas and xanthomas may histologically resemble LL with a dense dermal infiltrate of foamy histiocytes. No organisms are found in the infiltrate. Histologically, xanthogranulomas (juvenile or adult) will be a mixed infiltrate with foamy histiocytes; giant cell formation, especially Touton giant cells; lymphocytes; and granulocytes (Figure 3). Touton giant cells have a wreathlike formation of nuclei and an outer vacuolated cytoplasm. Xanthomas have sheets of large histiocytes with a foamy, lipid-filled interior and mild lymphocytic infiltrate (Figure 4).

Lepromatous Leprosy

Lepromatous leprosy (LL) is a chronic, cutaneous, granulomatous infection caused by Mycobacterium leprae or the newly discovered Mycobacterium lepromatosis, both acid-fast, intracellular, bacillus bacterium.¹ Although decreasing in prevalence due to effective treatment with antimicrobials, LL continues to be endemic in warm tropical or subtropical areas in Southeast Asia, sub-Saharan Africa, the Indian subcontinent, and South America.¹ The mode of transmission of infection is not well established.

The cutaneous manifestation of leprosy was previously classified based on the cell-mediated immune response of the patient, as described by Ridley and Jopling,² ranging from tuberculoid leprosy (TT) to LL. In this spectrum of leprosy are the borderline lesions including borderline tuberculoid, borderline, and borderline lepromatous.^2,3 Although this classification is popular, in 2012 the World Health Organization implemented a new 2-category classification system to standardize treatment regimens: paucibacillary (2–5 lesions or 1 nerve involvement) and multibacillary (>5 lesions or multiple nerve involvement).⁴

In LL, a cell-mediated immune response is not mounted against the infection in the patient. Clinically, the disease can manifest as macular and nodular erythematous cutaneous lesions with poorly defined borders that are preferentially located on the face, earlobes, and nasal mucosa. Chronic infections are associated with sensory loss. Histologically, the dermis is densely infiltrated by foamy macrophages (Virchow cells or lepra cells), which do not form granulomas (quiz image A). The infiltrate may have varying accompanying lymphocytes and plasma cells, which can extend deep into the subcutaneous adipose tissue. Between the dermal infiltrate and epidermis is an uninvolved band of superficial dermis called the Grenz zone. The epidermis is flattened and atrophic. Nerves often are surrounded by macrophages with degrees of hyalinization but rarely are swollen. On acid-fast staining (Wade-Fite or Ziehl-Neelsen), numerous acid-fast bacilli are present within dermal cells in densely packed, intracellular collections called globi (quiz image B).^2,3,5

In TT, the robust immune response causes epithelioid granuloma formation, similar to cutaneous sarcoidosis, and few, if any, organisms can be found on special stains. The remaining borderline lesions have varying numbers of bacilli and varying amounts of granuloma formation.^3,6,7 Many cases of TT resolve without specific treatment. For most leprous diseases, the World Health Organization currently recommends a regimen of dapsone, rifampin, and clofazimine combination treatments for 6 to 12 months depending on the type of leprosy.⁸

Cutaneous leishmaniasis should be included in the differential diagnosis for patients from LL endemic areas. Early lesions can have a histiocytic infiltration with associated mixed inflammation and prominent epidermal hyperplasia. These early lesions usually have parasitic organisms located within the periphery of the cytoplasm of macrophages (“marquee sign”) to help differentiate it from leprous diseases (Figure 1).⁹

In nonendemic areas, leprous diseases often are mistaken for sarcoidosis, xanthomas, granular cell tumors, paraffinomas, or other histiocytic-rich lesions.¹⁰ Cutaneous sarcoidosis may be difficult to distinguish from TT, as both have noncaseating granulomas (Figure 2). Rare acid-fast bacilli may aid in the diagnosis, and sarcoid granulomas are not typically associated with cutaneous nerve involvement. New diagnostic tools such as polymerase chain reaction or genome sequencing can pick up rare organisms.

Xanthogranuolomas and xanthomas may histologically resemble LL with a dense dermal infiltrate of foamy histiocytes. No organisms are found in the infiltrate. Histologically, xanthogranulomas (juvenile or adult) will be a mixed infiltrate with foamy histiocytes; giant cell formation, especially Touton giant cells; lymphocytes; and granulocytes (Figure 3). Touton giant cells have a wreathlike formation of nuclei and an outer vacuolated cytoplasm. Xanthomas have sheets of large histiocytes with a foamy, lipid-filled interior and mild lymphocytic infiltrate (Figure 4).

Lepromatous Leprosy

Lepromatous leprosy (LL) is a chronic, cutaneous, granulomatous infection caused by Mycobacterium leprae or the newly discovered Mycobacterium lepromatosis, both acid-fast, intracellular, bacillus bacterium.¹ Although decreasing in prevalence due to effective treatment with antimicrobials, LL continues to be endemic in warm tropical or subtropical areas in Southeast Asia, sub-Saharan Africa, the Indian subcontinent, and South America.¹ The mode of transmission of infection is not well established.

The cutaneous manifestation of leprosy was previously classified based on the cell-mediated immune response of the patient, as described by Ridley and Jopling,² ranging from tuberculoid leprosy (TT) to LL. In this spectrum of leprosy are the borderline lesions including borderline tuberculoid, borderline, and borderline lepromatous.^2,3 Although this classification is popular, in 2012 the World Health Organization implemented a new 2-category classification system to standardize treatment regimens: paucibacillary (2–5 lesions or 1 nerve involvement) and multibacillary (>5 lesions or multiple nerve involvement).⁴

In LL, a cell-mediated immune response is not mounted against the infection in the patient. Clinically, the disease can manifest as macular and nodular erythematous cutaneous lesions with poorly defined borders that are preferentially located on the face, earlobes, and nasal mucosa. Chronic infections are associated with sensory loss. Histologically, the dermis is densely infiltrated by foamy macrophages (Virchow cells or lepra cells), which do not form granulomas (quiz image A). The infiltrate may have varying accompanying lymphocytes and plasma cells, which can extend deep into the subcutaneous adipose tissue. Between the dermal infiltrate and epidermis is an uninvolved band of superficial dermis called the Grenz zone. The epidermis is flattened and atrophic. Nerves often are surrounded by macrophages with degrees of hyalinization but rarely are swollen. On acid-fast staining (Wade-Fite or Ziehl-Neelsen), numerous acid-fast bacilli are present within dermal cells in densely packed, intracellular collections called globi (quiz image B).^2,3,5

In TT, the robust immune response causes epithelioid granuloma formation, similar to cutaneous sarcoidosis, and few, if any, organisms can be found on special stains. The remaining borderline lesions have varying numbers of bacilli and varying amounts of granuloma formation.^3,6,7 Many cases of TT resolve without specific treatment. For most leprous diseases, the World Health Organization currently recommends a regimen of dapsone, rifampin, and clofazimine combination treatments for 6 to 12 months depending on the type of leprosy.⁸

Cutaneous leishmaniasis should be included in the differential diagnosis for patients from LL endemic areas. Early lesions can have a histiocytic infiltration with associated mixed inflammation and prominent epidermal hyperplasia. These early lesions usually have parasitic organisms located within the periphery of the cytoplasm of macrophages (“marquee sign”) to help differentiate it from leprous diseases (Figure 1).⁹

In nonendemic areas, leprous diseases often are mistaken for sarcoidosis, xanthomas, granular cell tumors, paraffinomas, or other histiocytic-rich lesions.¹⁰ Cutaneous sarcoidosis may be difficult to distinguish from TT, as both have noncaseating granulomas (Figure 2). Rare acid-fast bacilli may aid in the diagnosis, and sarcoid granulomas are not typically associated with cutaneous nerve involvement. New diagnostic tools such as polymerase chain reaction or genome sequencing can pick up rare organisms.

Xanthogranuolomas and xanthomas may histologically resemble LL with a dense dermal infiltrate of foamy histiocytes. No organisms are found in the infiltrate. Histologically, xanthogranulomas (juvenile or adult) will be a mixed infiltrate with foamy histiocytes; giant cell formation, especially Touton giant cells; lymphocytes; and granulocytes (Figure 3). Touton giant cells have a wreathlike formation of nuclei and an outer vacuolated cytoplasm. Xanthomas have sheets of large histiocytes with a foamy, lipid-filled interior and mild lymphocytic infiltrate (Figure 4).

How does the global period affect dermatologists?

Global period is a term used to describe what is included in the payment for performance of a procedure using Current Procedural Terminology (CPT) codes. These global periods can either be 0 (000), 10 (010), or 90 (090) days. In dermatology, we have all three. Most codes used by dermatologists fall under global periods of 0 and 10 days, while 90-day codes are used for all adjacent tissue transfers and split- and full-thickness grafts. In documents listing global periods for CPT codes,¹ you also may see “XXX” when the global period concept does not apply to a particular code, “YYY” when the payer decides on whether a global period applies and what it will be, and “ZZZ” when a certain code is an add-on to another service and is therefore included in the global period for that service.

The contents of a service are defined by the global period. Although the procedure itself is an obvious component, CPT codes with a global period of 000 (eg, biopsy of a skin lesion, simple repairs) have no preoperative or postoperative periods, and an evaluation and management (E&M) service usually is not payable if it was done in relation to the procedure. If the patient returns the following day for any reason, including concerns about the procedure itself, these visits may be reported separately.

For CPT codes with global periods of 010 (eg, excisions, intermediate and complex repairs, destructions), there also is no preoperative period and a visit on the day of the procedure generally is not payable as a separate service. The day of the procedure and the 10 days after are included in the global period, and any visits relating to the procedure on that day and the 10 days following the procedure are not payable separately. Typically, the value of one 99212 or 99213 E&M visit is included in the payment for the procedure.

For CPT codes with global periods of 090, the day before the procedure, the day of the procedure, and 90 days following the procedure are all included. Typically, more than one established patient visit along with hospital management and discharge planning where deemed necessary by the Centers for Medicare & Medicaid Services (CMS) are included, which seems straightforward, but there is a sort of paradox here. An initial evaluation by the surgeon who determines the need for the 090 code (by definition, 090 means major surgery and major surgery means 090) can be separately reported for E&M using modifier -57 (decision for surgery), which means the surgeon seeing the hot abdomen in the emergency department can report an E&M code in addition to the procedure, as can the surgeon who decides to repair a defect after removal of a skin tumor with a flap or graft. The same is not applicable if one performs a simple repair (included with benign or malignant excisions) following Mohs micrographic surgery or an intermediate or complex repair after any form of skin cancer removal. In any event, you are making a decision about what repair is best for the patient and sharing that with him/her while obtaining patient consent, but only 090 codes allow the capture of the decision to perform the procedure.

Which modifiers can you use on the same day as a procedure during the global period?

All is not lost if you perform other activities on the same day as the procedure or during the global period if those other activities are unrelated, which means complications of the procedure cannot be separately reported. If the unrelated cognitive work is reported on the day of a procedure with an E&M code, it should be accompanied by modifier -25 (significant, separately identifiable E&M service by the same physician or other qualified health care professional on the same day of the procedure or other service). If you have an E&M visit unrelated to the procedure within the global period, report it using modifier -24 (unrelated E&M service by the same physician or other qualified health care professional during a postoperative period).

If you perform another procedure on the same day as the primary one, you can use modifier -51 (multiple procedures) to let the payer know you provided other services that are separately reportable. If you do multiples of the same procedure, use modifier -59 (distinct procedural service) to let the payer know that you indeed did multiple procedures and did not submit a typographical error. Modifier -59 also is used when you perform a pair of procedures on separate and distinct lesions that would be disallowed by Mutually Exclusive Edits if done on a single lesion. For example, if you perform a biopsy of a lesion and immediately curette it, you should wait for the pathology report; if the lesion is malignant, only the destruction should be reported, and if it is benign, the only medically necessary service was the biopsy. When biopsy and curettage are performed on 2 separate lesions on the same date of service, payer software will disallow the biopsy charge unless a -59 modifier is attached to indicate that the biopsy was performed on a separate lesion. Medicare has introduced the -XS modifier, which is planned to be phased in to replace the -59 modifier for Medicare patients,² if and when the CMS sets up their systems to accept the modifier.

If you repeat a procedure during the global period (eg, reexcision for a positive margin), it is appropriate to use modifier -58 (staged or related procedure or service by the same physician or other qualified health care professional during the postoperative period). If an unrelated procedure is performed during the global period, such as removing another lesion at a different site, modifier -79 (unrelated procedure or service by the same physician or other qualified health care professional during the postoperative period) lets you report it.

There are 2 available modifiers that you might think twice before using. Modifier -76 (repeat procedure or service by same physician or other qualified health care professional) may be used if, for example, a wound opens and you have to sew it up again. The more common usage is more pedestrian; a second electrocardiogram reading on the same day is a common use.³ Modifier -78 (unplanned return to the operating/procedure room by the same physician or other qualified health care professional following initial procedure for a related procedure during the postoperative period) is used when something goes awry, such as an aneurysm repair that is bleeding postoperatively, necessitating a trip back to the operating room.⁴

How might these modifiers be used in dermatology? One example may be if a wound dehisces or needs to be seen for a bleeding issue that might necessitate opening and exploring the wound; if a patient has one of these problems after fixing the plumbing and hits himself with a wrench, use of these modifiers is reasonable. On the other hand, if the patient is waiting in your office to be picked up and the problem happens, using these modifiers may not be the wisest thing to do. Let common sense prevail!

What is CPT code 99024?

Likely a code you have never used in your private office, the descriptor for 99024 states “postoperative follow-up visit, normally included in the surgical package, to indicate that an E&M service was performed during a postoperative period for a reason(s) related to the original procedure,” which translates to “here for an included visit so why am I billing this and having the cost of a claim with no reimbursement?” Why indeed. You may be using it as a space holder—one more check and balance so no patient leaves the office without a superbill or its electronic equivalent being submitted to your billing staff—or you may simply never use it. The CMS is interested in it as a way to see if the visits embedded in global periods actually take place. This is especially important as CMS is legally mandated under the Medicare Access and CHIP Reauthorization Act of 2015 (MACRA)⁵ to see if these visits actually take place.⁶ There are billions of dollars paid out for visits that are part of the global package and this code is one way the government may track them. If you are not using this code at all, you might consider it, even if you do not submit a claim. Your staff will know you did not forget to report a service and the reporting of the code by you internally and it lets you document for the billing side of the practice that they were there and a code report has been performed and not simply forgotten.

Final Thoughts

Following this discussion of global periods and CPT code 99024, you may be wondering why you get paid what you do and how the visits all link together. The buzzword is intensity, and we will explore that concept and IWPUT (intraservice work per unit of time), which I have coined as meaning “I Will Persevere Until Then,” in the next column.

How does the global period affect dermatologists?

Global period is a term used to describe what is included in the payment for performance of a procedure using Current Procedural Terminology (CPT) codes. These global periods can either be 0 (000), 10 (010), or 90 (090) days. In dermatology, we have all three. Most codes used by dermatologists fall under global periods of 0 and 10 days, while 90-day codes are used for all adjacent tissue transfers and split- and full-thickness grafts. In documents listing global periods for CPT codes,¹ you also may see “XXX” when the global period concept does not apply to a particular code, “YYY” when the payer decides on whether a global period applies and what it will be, and “ZZZ” when a certain code is an add-on to another service and is therefore included in the global period for that service.

The contents of a service are defined by the global period. Although the procedure itself is an obvious component, CPT codes with a global period of 000 (eg, biopsy of a skin lesion, simple repairs) have no preoperative or postoperative periods, and an evaluation and management (E&M) service usually is not payable if it was done in relation to the procedure. If the patient returns the following day for any reason, including concerns about the procedure itself, these visits may be reported separately.

For CPT codes with global periods of 010 (eg, excisions, intermediate and complex repairs, destructions), there also is no preoperative period and a visit on the day of the procedure generally is not payable as a separate service. The day of the procedure and the 10 days after are included in the global period, and any visits relating to the procedure on that day and the 10 days following the procedure are not payable separately. Typically, the value of one 99212 or 99213 E&M visit is included in the payment for the procedure.

For CPT codes with global periods of 090, the day before the procedure, the day of the procedure, and 90 days following the procedure are all included. Typically, more than one established patient visit along with hospital management and discharge planning where deemed necessary by the Centers for Medicare & Medicaid Services (CMS) are included, which seems straightforward, but there is a sort of paradox here. An initial evaluation by the surgeon who determines the need for the 090 code (by definition, 090 means major surgery and major surgery means 090) can be separately reported for E&M using modifier -57 (decision for surgery), which means the surgeon seeing the hot abdomen in the emergency department can report an E&M code in addition to the procedure, as can the surgeon who decides to repair a defect after removal of a skin tumor with a flap or graft. The same is not applicable if one performs a simple repair (included with benign or malignant excisions) following Mohs micrographic surgery or an intermediate or complex repair after any form of skin cancer removal. In any event, you are making a decision about what repair is best for the patient and sharing that with him/her while obtaining patient consent, but only 090 codes allow the capture of the decision to perform the procedure.

Which modifiers can you use on the same day as a procedure during the global period?

All is not lost if you perform other activities on the same day as the procedure or during the global period if those other activities are unrelated, which means complications of the procedure cannot be separately reported. If the unrelated cognitive work is reported on the day of a procedure with an E&M code, it should be accompanied by modifier -25 (significant, separately identifiable E&M service by the same physician or other qualified health care professional on the same day of the procedure or other service). If you have an E&M visit unrelated to the procedure within the global period, report it using modifier -24 (unrelated E&M service by the same physician or other qualified health care professional during a postoperative period).

If you perform another procedure on the same day as the primary one, you can use modifier -51 (multiple procedures) to let the payer know you provided other services that are separately reportable. If you do multiples of the same procedure, use modifier -59 (distinct procedural service) to let the payer know that you indeed did multiple procedures and did not submit a typographical error. Modifier -59 also is used when you perform a pair of procedures on separate and distinct lesions that would be disallowed by Mutually Exclusive Edits if done on a single lesion. For example, if you perform a biopsy of a lesion and immediately curette it, you should wait for the pathology report; if the lesion is malignant, only the destruction should be reported, and if it is benign, the only medically necessary service was the biopsy. When biopsy and curettage are performed on 2 separate lesions on the same date of service, payer software will disallow the biopsy charge unless a -59 modifier is attached to indicate that the biopsy was performed on a separate lesion. Medicare has introduced the -XS modifier, which is planned to be phased in to replace the -59 modifier for Medicare patients,² if and when the CMS sets up their systems to accept the modifier.

If you repeat a procedure during the global period (eg, reexcision for a positive margin), it is appropriate to use modifier -58 (staged or related procedure or service by the same physician or other qualified health care professional during the postoperative period). If an unrelated procedure is performed during the global period, such as removing another lesion at a different site, modifier -79 (unrelated procedure or service by the same physician or other qualified health care professional during the postoperative period) lets you report it.

There are 2 available modifiers that you might think twice before using. Modifier -76 (repeat procedure or service by same physician or other qualified health care professional) may be used if, for example, a wound opens and you have to sew it up again. The more common usage is more pedestrian; a second electrocardiogram reading on the same day is a common use.³ Modifier -78 (unplanned return to the operating/procedure room by the same physician or other qualified health care professional following initial procedure for a related procedure during the postoperative period) is used when something goes awry, such as an aneurysm repair that is bleeding postoperatively, necessitating a trip back to the operating room.⁴

How might these modifiers be used in dermatology? One example may be if a wound dehisces or needs to be seen for a bleeding issue that might necessitate opening and exploring the wound; if a patient has one of these problems after fixing the plumbing and hits himself with a wrench, use of these modifiers is reasonable. On the other hand, if the patient is waiting in your office to be picked up and the problem happens, using these modifiers may not be the wisest thing to do. Let common sense prevail!

What is CPT code 99024?

Likely a code you have never used in your private office, the descriptor for 99024 states “postoperative follow-up visit, normally included in the surgical package, to indicate that an E&M service was performed during a postoperative period for a reason(s) related to the original procedure,” which translates to “here for an included visit so why am I billing this and having the cost of a claim with no reimbursement?” Why indeed. You may be using it as a space holder—one more check and balance so no patient leaves the office without a superbill or its electronic equivalent being submitted to your billing staff—or you may simply never use it. The CMS is interested in it as a way to see if the visits embedded in global periods actually take place. This is especially important as CMS is legally mandated under the Medicare Access and CHIP Reauthorization Act of 2015 (MACRA)⁵ to see if these visits actually take place.⁶ There are billions of dollars paid out for visits that are part of the global package and this code is one way the government may track them. If you are not using this code at all, you might consider it, even if you do not submit a claim. Your staff will know you did not forget to report a service and the reporting of the code by you internally and it lets you document for the billing side of the practice that they were there and a code report has been performed and not simply forgotten.

Final Thoughts

Following this discussion of global periods and CPT code 99024, you may be wondering why you get paid what you do and how the visits all link together. The buzzword is intensity, and we will explore that concept and IWPUT (intraservice work per unit of time), which I have coined as meaning “I Will Persevere Until Then,” in the next column.

How does the global period affect dermatologists?

Global period is a term used to describe what is included in the payment for performance of a procedure using Current Procedural Terminology (CPT) codes. These global periods can either be 0 (000), 10 (010), or 90 (090) days. In dermatology, we have all three. Most codes used by dermatologists fall under global periods of 0 and 10 days, while 90-day codes are used for all adjacent tissue transfers and split- and full-thickness grafts. In documents listing global periods for CPT codes,¹ you also may see “XXX” when the global period concept does not apply to a particular code, “YYY” when the payer decides on whether a global period applies and what it will be, and “ZZZ” when a certain code is an add-on to another service and is therefore included in the global period for that service.

The contents of a service are defined by the global period. Although the procedure itself is an obvious component, CPT codes with a global period of 000 (eg, biopsy of a skin lesion, simple repairs) have no preoperative or postoperative periods, and an evaluation and management (E&M) service usually is not payable if it was done in relation to the procedure. If the patient returns the following day for any reason, including concerns about the procedure itself, these visits may be reported separately.

For CPT codes with global periods of 010 (eg, excisions, intermediate and complex repairs, destructions), there also is no preoperative period and a visit on the day of the procedure generally is not payable as a separate service. The day of the procedure and the 10 days after are included in the global period, and any visits relating to the procedure on that day and the 10 days following the procedure are not payable separately. Typically, the value of one 99212 or 99213 E&M visit is included in the payment for the procedure.

For CPT codes with global periods of 090, the day before the procedure, the day of the procedure, and 90 days following the procedure are all included. Typically, more than one established patient visit along with hospital management and discharge planning where deemed necessary by the Centers for Medicare & Medicaid Services (CMS) are included, which seems straightforward, but there is a sort of paradox here. An initial evaluation by the surgeon who determines the need for the 090 code (by definition, 090 means major surgery and major surgery means 090) can be separately reported for E&M using modifier -57 (decision for surgery), which means the surgeon seeing the hot abdomen in the emergency department can report an E&M code in addition to the procedure, as can the surgeon who decides to repair a defect after removal of a skin tumor with a flap or graft. The same is not applicable if one performs a simple repair (included with benign or malignant excisions) following Mohs micrographic surgery or an intermediate or complex repair after any form of skin cancer removal. In any event, you are making a decision about what repair is best for the patient and sharing that with him/her while obtaining patient consent, but only 090 codes allow the capture of the decision to perform the procedure.

Which modifiers can you use on the same day as a procedure during the global period?

All is not lost if you perform other activities on the same day as the procedure or during the global period if those other activities are unrelated, which means complications of the procedure cannot be separately reported. If the unrelated cognitive work is reported on the day of a procedure with an E&M code, it should be accompanied by modifier -25 (significant, separately identifiable E&M service by the same physician or other qualified health care professional on the same day of the procedure or other service). If you have an E&M visit unrelated to the procedure within the global period, report it using modifier -24 (unrelated E&M service by the same physician or other qualified health care professional during a postoperative period).

If you perform another procedure on the same day as the primary one, you can use modifier -51 (multiple procedures) to let the payer know you provided other services that are separately reportable. If you do multiples of the same procedure, use modifier -59 (distinct procedural service) to let the payer know that you indeed did multiple procedures and did not submit a typographical error. Modifier -59 also is used when you perform a pair of procedures on separate and distinct lesions that would be disallowed by Mutually Exclusive Edits if done on a single lesion. For example, if you perform a biopsy of a lesion and immediately curette it, you should wait for the pathology report; if the lesion is malignant, only the destruction should be reported, and if it is benign, the only medically necessary service was the biopsy. When biopsy and curettage are performed on 2 separate lesions on the same date of service, payer software will disallow the biopsy charge unless a -59 modifier is attached to indicate that the biopsy was performed on a separate lesion. Medicare has introduced the -XS modifier, which is planned to be phased in to replace the -59 modifier for Medicare patients,² if and when the CMS sets up their systems to accept the modifier.

If you repeat a procedure during the global period (eg, reexcision for a positive margin), it is appropriate to use modifier -58 (staged or related procedure or service by the same physician or other qualified health care professional during the postoperative period). If an unrelated procedure is performed during the global period, such as removing another lesion at a different site, modifier -79 (unrelated procedure or service by the same physician or other qualified health care professional during the postoperative period) lets you report it.

There are 2 available modifiers that you might think twice before using. Modifier -76 (repeat procedure or service by same physician or other qualified health care professional) may be used if, for example, a wound opens and you have to sew it up again. The more common usage is more pedestrian; a second electrocardiogram reading on the same day is a common use.³ Modifier -78 (unplanned return to the operating/procedure room by the same physician or other qualified health care professional following initial procedure for a related procedure during the postoperative period) is used when something goes awry, such as an aneurysm repair that is bleeding postoperatively, necessitating a trip back to the operating room.⁴

How might these modifiers be used in dermatology? One example may be if a wound dehisces or needs to be seen for a bleeding issue that might necessitate opening and exploring the wound; if a patient has one of these problems after fixing the plumbing and hits himself with a wrench, use of these modifiers is reasonable. On the other hand, if the patient is waiting in your office to be picked up and the problem happens, using these modifiers may not be the wisest thing to do. Let common sense prevail!

What is CPT code 99024?

Likely a code you have never used in your private office, the descriptor for 99024 states “postoperative follow-up visit, normally included in the surgical package, to indicate that an E&M service was performed during a postoperative period for a reason(s) related to the original procedure,” which translates to “here for an included visit so why am I billing this and having the cost of a claim with no reimbursement?” Why indeed. You may be using it as a space holder—one more check and balance so no patient leaves the office without a superbill or its electronic equivalent being submitted to your billing staff—or you may simply never use it. The CMS is interested in it as a way to see if the visits embedded in global periods actually take place. This is especially important as CMS is legally mandated under the Medicare Access and CHIP Reauthorization Act of 2015 (MACRA)⁵ to see if these visits actually take place.⁶ There are billions of dollars paid out for visits that are part of the global package and this code is one way the government may track them. If you are not using this code at all, you might consider it, even if you do not submit a claim. Your staff will know you did not forget to report a service and the reporting of the code by you internally and it lets you document for the billing side of the practice that they were there and a code report has been performed and not simply forgotten.

Final Thoughts

Following this discussion of global periods and CPT code 99024, you may be wondering why you get paid what you do and how the visits all link together. The buzzword is intensity, and we will explore that concept and IWPUT (intraservice work per unit of time), which I have coined as meaning “I Will Persevere Until Then,” in the next column.

Rosacea is a chronic skin disease characterized by flushing, erythema, telangiectasia, papules, and pustules in the central face region.¹ It most often affects middle-aged women (age range, 30–50 years).² Rosacea is rare in the pediatric population, especially before puberty.³ There are 3 subtypes of pediatric rosacea: vascular, papulopustular, and ocular. Phymatous/rhinophymatous rosacea is only seen in the adult population.³ Recommendations for the management of pediatric rosacea heavily rely on data from retrospective chart reviews and case series.

Etiology of Pediatric Rosacea

Rosacea is thought to be a consequence of vasomotor instability in both adults and children. A family history of rosacea is sometimes reported in patients with pediatric rosacea.⁴ Patients often are sensitive to heat, sunlight, topical corticosteroids, spicy foods, hot liquids, and certain soaps and cleansers.^1,3,4 In a review of the literature by Vemuri et al,⁵ the various reported triggers of rosacea include harsh climates that damage the blood vessels and dermal connective tissue, defects in the endothelium and dermal matrix, perivascular inflammation, orally ingested chemicals, changes in the flora of the hair follicles, excessive antimicrobial peptides, and the presence of free radicals. Overall, it is unclear which of these factors are triggers of pediatric rosacea.

The molecular basis of rosacea has been elucidated. It is well known that rosacea patients have higher levels of cathelicidins in the facial skin. Furthermore, they appear to have different processed forms of cathelicidin peptides compared to adults without rosacea, possibly due to changes in posttranslational processing.⁶ One such peptide, cathelicidin LL-37, also has been implicated in atopic dermatitis⁷ and psoriasis.⁸ Its role in rosacea appears to be multifaceted. Cathelicidin LL-37 helps to attract neutrophils, monocytes, and T lymphocytes, and also has antimicrobial properties; therefore, it plays a role in both the innate and adaptive immune systems.⁹ Cathelicidin LL-37 also has been implicated in inducing angiogenesis¹⁰ and suppressing dermal fibroblasts.¹¹

Muto et al¹² found that there is an increased number of mast cells in the dermis of patients with rosacea. Mast cells contribute to vasodilation, angiogenesis, and the recruitment of other inflammatory cells.¹² Importantly, human mast cells are a source of cathelicidins including cathelicidin LL-37; these proteins play a vital role in the antimicrobial capabilities of mast cells.¹³

Clinical Presentation and Comorbidities

Vascular rosacea presents with characteristic flushing and erythema, which lasts more than a few minutes as compared to physiologic erythema,¹ and sometimes telangiectasia is seen.³ The cheeks, chin, and nasolabial folds are most commonly involved.² In papulopustular rosacea, papules and pustules are seen overlying the erythema.^1,3 Open and closed comedones also have been documented in case reports but are not commonly seen.² Pediatric rosacea often begins with flushing of the face and then progresses to the development of papules and pustules.⁴

Ocular rosacea can occur with or without cutaneous findings. In a retrospective study of 20 pediatric patients (aged 1–15 years), 11 (55%) patients had both ocular and cutaneous rosacea, 3 (15%) only had ocular symptoms, and 6 (30%) only had cutaneous symptoms. The most common form of rosacea in this study was papulopustular rosacea.¹⁴ Ocular symptoms often are bilateral¹⁵ and can include blepharitis, conjunctival injection, recurrent chalazion, conjunctivitis,² and less commonly corneal ulceration and scarring.¹⁶ Patients also may report photophobia or a foreign body sensation.¹⁷ Importantly, ocular symptoms often precede the cutaneous symptoms and can delay the diagnosis of rosacea,^14,16,18 as these symptoms often are misdiagnosed as viral or bacterial infections.¹⁵ Fortunately, ocular disease responds well to treatment if diagnosed early.

Weston and Morelli¹⁹ conducted a retrospective study of 106 children (46 males; 60 females) 13 years and younger with steroid rosacea; 29 children were younger than 3 years. A family history of rosacea was present in 20% of participants, and prior use of class 7 steroids was reported in 54%, whereas only 3% had used class 1 topical steroids. Ninety-eight participants had perinasal involvement, 94 had perioral involvement, and 44 had periorbital involvement of the lower eyelids.¹⁹

Rosacea fulminans (also known as pyoderma faciale) is a rare acute-onset eruption typically found in young women in their 20s and 30s.²⁰ Rosacea fulminans is characterized by papules, pustules, nodules, cysts, draining sinuses, communicating sinus tracts, and less commonly comedones.^20,21 The skin can appear erythematous, cyanotic, or dull red.²¹ Most of the lesions are found on the face, particularly on the forehead, cheeks, nose, and chin,²¹ but lesions on the chest and back have been documented in adult patients.²⁰ In an examination of prior case series, most patients were otherwise healthy. There are case reports documenting rosacea fulminans in teenagers,²⁰ but the youngest patient recorded was an otherwise healthy 3-year-old girl who developed a sudden onset of erythematous papules, pustules, cysts, and purulent discharging sinuses on the cheeks that spread to the chin, perioral, and paranasal areas.²¹

Differential Diagnosis

Rosacea is rare in children, so other papulopustular disorders must be ruled out, including acne vulgaris, periorificial/perioral dermatitis, sarcoidosis, systemic lupus erythematosus, steroid-induced rosacea, ataxia telangiectasia, and demodicosis.

Acne vulgaris commonly presents in older adolescents and teenagers with open and closed comedones, inflammatory papules, and pustules.² Intense facial flushing and telangiectasia usually is not seen.

In perioral dermatitis, skin lesions often are clustered around the mouth, nose, and eyes. Typically there are no telangiectases or ocular complications.³ Facial flushing and telangiectases are uncommon, except in steroid-induced perioral dermatitis.²

The cutaneous findings of sarcoidosis include red-brown papules on the face and lips, and patients also may have ocular involvement such as uveitis and iritis.³ However, there are typically other systemic findings such as pulmonary symptoms, weight loss, fatigue, lethargy, fever, and erythema nodosum.^2,3 Chest radiograph findings (eg, bilateral hilar lym-phadenopathy), ophthalmologic examination, and laboratory data (eg, elevated alkaline phosphate and/or elevated angiotensin-converting enzyme) can help confirm or rule out the diagnosis of sarcoidosis.^2,3

Unlike systemic lupus erythematosus, patients with rosacea will have involvement of sun-protected areas of the skin. Patients with systemic lupus erythematosus typically report arthralgia and severe photosensitivity and will have elevated antinuclear antibody titers. Skin biopsies and immunofluorescence can help confirm the diagnosis.³ Importantly, some patients with rosacea will have a positive lupus band test.^22,23

Steroid-induced rosacea typically occurs 2 weeks after discontinuing therapy with topical fluorinated glucocorticosteroids.²⁴ Children present with monomorphic papules, pustules, and telangiectases⁴ on the eyelids and lateral face as opposed to the central face regions.²⁴

Ataxia telangiectasia can present with telangiectases, skin atrophy, café au lait spots, and premature graying.²⁵ A 15-year-old adolescent girl with ataxia telangiectasia presented with granulomatous acne rosacea that improved after 4 weeks of treatment with isotretinoin 0.5 mg/kg daily. The lesions cleared almost completely after 5 months.²⁵

Demodicosis is a disorder of the pilosebaceous units caused by the human Demodex mite.²⁶ It typically involves the periorificial regions in adults and the elderly population. Patients can present with fine, white-yellow, scaly changes of the sebaceous hair follicles, with minimal erythema and inflammation. Papules and pustules also can be present.²⁶

Diagnosis and Histopathology

Because rosacea is rare in children, it is important to thoroughly evaluate other possible diagnoses. The diagnosis of pediatric rosacea is clinical and biopsies are rarely performed. Laboratory tests such as cultures generally are not useful.

Marks and Harcourt-Webster²⁷ reviewed the biopsies of 108 adult patients with rosacea. The biopsies of patients with predominantly erythema and telangiectasia showed evidence of vascular dilatation with a perivascular infiltrate composed predominantly of lymphocytes and 39 specimens that were compared to controls showed more solar elastosis. Biopsies of papular rosacea contained inflammatory infiltrates in the upper and mid dermis composed primarily of lymphocytes and histiocytes. In some patients, neutrophils, plasma cells, and giant cells also were observed. Hair follicle abnormalities were present in 20% of the biopsies, with 19% showing evidence of the Demodex mite. Vascular dilatation also was common. Overall, common findings included lymphohistiocytic infiltrates around the blood vessels of the upper dermis, dilated vessels, edema, elastosis, and disorganization of connective tissue in the upper dermis.

Helm et al²⁸ reviewed histopathologic patterns from 53 patients with granulomatous rosacea. Findings included a mixed lymphohistiocytic infiltrate (predominantly lymphocytic in 40% of patients and predominantly histiocytic with occasional giant cells in 34% of patients), epithelioid granulomas (11% of patients), and epithelioid granulomas with caseation necrosis (11% of patients).

The histopathology of rosacea fulminans is characterized by dense perivascular and periadnexal infiltrates composed of granulocytes, eosinophils, and epithelioid granulomas, as well as panniculitis.²⁰

Treatment and Clinical Outcomes

Certain lifestyle recommendations are integral components of disease management, including avoidance of triggers such as extreme temperatures, hot drinks, spicy food, and topical agents that could be irritating (especially topical corticosteroids).²⁹ Patients should be advised to use daily sunscreen containing physical blockers such as titanium dioxide or zinc oxide. Teenagers should avoid the use of cosmetics and makeup, especially products containing sodium lauryl sulfate, menthol, and camphor. Daily use of emollients can help some patients.²⁹

There are both topical and systemic therapies available for pediatric rosacea; however, most of the data are based on the use of these treatments in the adult population. Patients with mild to moderate disease often can be managed using topical agents. Metronidazole (0.75% cream, 1% gel, or 0.75% lotion) has been studied extensively in adult patients, and when used once daily for 12 weeks, it has been able to control moderate to severe disease.^30,31 In one study conducted in adult patients, topical metronidazole was able to maintain remission in adults who had previously been treated with a combination of oral tetracycline and metronidazole gel.³¹ Sodium sulfacetamide 10%–sulfur 5% (cleanser or lotion) has been successful in adult patients and often is used in combination with other therapies such as topical metronidazole.^32-34 Azelaic acid cream 20%,³⁵ benzoyl peroxide (wash or gel),²⁹ topical clindamycin,³⁶ topical erythromycin,^29,37 tacrolimus ointment 0.1%,³⁸ and tretinoin cream also have been studied in adults.^3,39 Several of these topical agents can cause irritation on application (eg, metronidazole, sulfur-based agents, azelaic acid, benzoyl peroxide, erythromycin, tretinoin).³

The use of systemic treatments in pediatric patients is heavily based on case reports and case series.^2,14,16,40 Therapies have included tetracycline (500 mg twice daily tapered to 250 mg daily),²⁹ minocycline (50–100 mg twice daily), doxycycline (50–100 mg twice daily or 4 times daily), erythromycin (30–50 mg/kg daily), clarithromycin (15 mg/kg twice daily for 4 weeks and then daily for 4 weeks), and azithromycin (5–10 mg/kg daily).³ Tetracycline antibiotics should not be used in children 8 years or younger.

In a case series by Drolet and Paller,² an 11-year-old girl was treated with tetracycline 500 mg (later tapered to 250 mg daily) and metronidazole gel 0.75%, both used twice daily. Previously, she had not responded to topical steroids, tretinoin cream 0.05%, benzoyl peroxide 5%, or systemic prednisone. After 6 weeks of treatment, the pustules and chalazion had resolved and she had only minimal erythema of the skin and conjunctiva. Sixteen months after the start of treatment, a regimen of tetracycline 250 mg daily and metronidazole gel resulted in disease clearance on the face.²

A 9-year-old girl with concurrent systemic lupus erythematosus was treated with tetracycline 250 mg and topical erythromycin 2%, both used twice daily.² After 4 weeks her face was clear. Four months later she developed new telangiectases and topical erythromycin was replaced with topical metronidazole. Eventually the dose of tetracycline was reduced to 250 mg daily.²

An 11-year-old boy with likely granulomatous rosacea was treated with erythromycin 250 mg 4 times daily, alclometasone dipropionate cream 0.05% twice daily, and topical clindamycin twice daily.² Marked improvement was noticed after 3 weeks of treatment. Metronidazole gel 0.75% was added and 3 months later the patient’s face was clear, without evidence of scarring. The dose of erythromycin was later reduced to 500 mg daily, and eventually the patient experienced clearance with the use of metronidazole gel daily.²

In another case series, 4 female patients (age range, 4–12 years) were treated with systemic erythromycin 20 mg/kg daily (ocular involvement only) or doxycycline 2.2 mg/kg daily used in two 12-year-old patients with ocular and cutaneous involvement for at least 12 months. All 4 patients showed considerable improvement within 1 month and remained free of disease throughout a mean follow-up period of 25.5 months.⁴⁰

As evidenced by these case reports, there is a wide array of treatments that have been used for pediatric rosacea. Although there are no formal evidence-based guidelines, there are certain considerations that must be taken into account when choosing treatment plans. Doxycycline and minocycline are known to cause less gastrointestinal upset than tetracycline with similar efficacy.⁴¹ Importantly, the tetracyclines are contraindicated in children younger than 9 years, as they can cause teeth staining and possibly affect skeletal growth.^3,4 When used in older children (age range, 9–12 years), patients must be advised not to take their medication with calcium or antacids.³ Clarithromycin and azithromycin tend to have fewer gastrointestinal side effects than erythromycin. Erythromycin and other macrolides can be used in children of all ages and in patients who are allergic to tetracyclines.³

Children with mild ocular symptoms often can control their disease with bacitracin and topical ocular antibiotics such as erythromycin.^2,15 For patients who require systemic antibiotics, various tetracyclines and macrolides have been used with success.^2,14-16,40

Adults with rosacea fulminans can require treatment with isotretinoin, oral antibiotics, and topical or even systemic corticosteroids.⁴² The 3-year-old girl with rosacea fulminans initially was treated with oral erythromycin (250 mg 4 times daily), oral prednisolone (0.5 mg/kg daily tapered over 2 weeks), fluocinolone acetonide cream 0.025%, and warm compresses with only moderate improvement.²¹ She was then started on oral isotretinoin (0.75 mg/kg daily) and within 4 weeks marked improvement was noted. After 8 weeks, the lesions had disappeared completely with only a few pitted scars remaining. Isotretinoin was continued for 24 weeks. One year after completion of treatment, she was still disease free.²¹

Weston and Morelli¹⁹ recommended the following treatment regimen for children with steroid rosacea: abrupt cessation of topical steroid use (as opposed to gradual withdrawal) and initiation of oral erythromycin stearate (30 mg/kg daily) in 2 daily doses for 4 weeks. Children who were unable to tolerate erythromycin (n=6) were told to use topical clindamycin phosphate twice daily for 4 weeks. Within 3 weeks 22% of patients had resolution, while 86% had resolution within 4 weeks. All of the patients cleared within 8 weeks. Importantly, there was no significant difference in duration of time until clearance between children who used the oral antibiotic or topical antibiotic.¹⁹

Conclusion

We know that the skin of rosacea patients contains higher levels of cathelicidins, which have been implicated in amplifying and contributing to the inflammatory response in several ways. Mast cells, which are a source of cathelicidins, also are increased in the skin of these patients. Children can present with vascular rosacea (characterized by flushing, erythema, and/or telangiectasia), papulopustular rosacea, or ocular rosacea. Common ocular symptoms include blepharitis, conjunctivitis, and recurrent chalazion. It is important to refer pediatric rosacea patients with ocular symptoms to an ophthalmologist to prevent ocular sequelae.

Rosacea is a clinical diagnosis but biopsy can be performed to rule out other diagnoses. Treatment consists of lifestyle modifications such as avoiding known triggers and the use of topical and/or oral agents. Common topical therapies include metronidazole and erythromycin. Systemic antibiotics include tetracycline, doxycycline, minocycline, azithromycin, and erythromycin. Some children are able to taper systemic agents and maintain disease control with topical therapy, while others may need to continue a low-dose antibiotic. Although flares can be controlled within weeks to months, rosacea is a chronic disorder and childhood rosacea tends to persist into adulthood.

Rosacea is a chronic skin disease characterized by flushing, erythema, telangiectasia, papules, and pustules in the central face region.¹ It most often affects middle-aged women (age range, 30–50 years).² Rosacea is rare in the pediatric population, especially before puberty.³ There are 3 subtypes of pediatric rosacea: vascular, papulopustular, and ocular. Phymatous/rhinophymatous rosacea is only seen in the adult population.³ Recommendations for the management of pediatric rosacea heavily rely on data from retrospective chart reviews and case series.

Etiology of Pediatric Rosacea

Rosacea is thought to be a consequence of vasomotor instability in both adults and children. A family history of rosacea is sometimes reported in patients with pediatric rosacea.⁴ Patients often are sensitive to heat, sunlight, topical corticosteroids, spicy foods, hot liquids, and certain soaps and cleansers.^1,3,4 In a review of the literature by Vemuri et al,⁵ the various reported triggers of rosacea include harsh climates that damage the blood vessels and dermal connective tissue, defects in the endothelium and dermal matrix, perivascular inflammation, orally ingested chemicals, changes in the flora of the hair follicles, excessive antimicrobial peptides, and the presence of free radicals. Overall, it is unclear which of these factors are triggers of pediatric rosacea.

The molecular basis of rosacea has been elucidated. It is well known that rosacea patients have higher levels of cathelicidins in the facial skin. Furthermore, they appear to have different processed forms of cathelicidin peptides compared to adults without rosacea, possibly due to changes in posttranslational processing.⁶ One such peptide, cathelicidin LL-37, also has been implicated in atopic dermatitis⁷ and psoriasis.⁸ Its role in rosacea appears to be multifaceted. Cathelicidin LL-37 helps to attract neutrophils, monocytes, and T lymphocytes, and also has antimicrobial properties; therefore, it plays a role in both the innate and adaptive immune systems.⁹ Cathelicidin LL-37 also has been implicated in inducing angiogenesis¹⁰ and suppressing dermal fibroblasts.¹¹

Muto et al¹² found that there is an increased number of mast cells in the dermis of patients with rosacea. Mast cells contribute to vasodilation, angiogenesis, and the recruitment of other inflammatory cells.¹² Importantly, human mast cells are a source of cathelicidins including cathelicidin LL-37; these proteins play a vital role in the antimicrobial capabilities of mast cells.¹³

Clinical Presentation and Comorbidities

Vascular rosacea presents with characteristic flushing and erythema, which lasts more than a few minutes as compared to physiologic erythema,¹ and sometimes telangiectasia is seen.³ The cheeks, chin, and nasolabial folds are most commonly involved.² In papulopustular rosacea, papules and pustules are seen overlying the erythema.^1,3 Open and closed comedones also have been documented in case reports but are not commonly seen.² Pediatric rosacea often begins with flushing of the face and then progresses to the development of papules and pustules.⁴

Ocular rosacea can occur with or without cutaneous findings. In a retrospective study of 20 pediatric patients (aged 1–15 years), 11 (55%) patients had both ocular and cutaneous rosacea, 3 (15%) only had ocular symptoms, and 6 (30%) only had cutaneous symptoms. The most common form of rosacea in this study was papulopustular rosacea.¹⁴ Ocular symptoms often are bilateral¹⁵ and can include blepharitis, conjunctival injection, recurrent chalazion, conjunctivitis,² and less commonly corneal ulceration and scarring.¹⁶ Patients also may report photophobia or a foreign body sensation.¹⁷ Importantly, ocular symptoms often precede the cutaneous symptoms and can delay the diagnosis of rosacea,^14,16,18 as these symptoms often are misdiagnosed as viral or bacterial infections.¹⁵ Fortunately, ocular disease responds well to treatment if diagnosed early.

Weston and Morelli¹⁹ conducted a retrospective study of 106 children (46 males; 60 females) 13 years and younger with steroid rosacea; 29 children were younger than 3 years. A family history of rosacea was present in 20% of participants, and prior use of class 7 steroids was reported in 54%, whereas only 3% had used class 1 topical steroids. Ninety-eight participants had perinasal involvement, 94 had perioral involvement, and 44 had periorbital involvement of the lower eyelids.¹⁹

Rosacea fulminans (also known as pyoderma faciale) is a rare acute-onset eruption typically found in young women in their 20s and 30s.²⁰ Rosacea fulminans is characterized by papules, pustules, nodules, cysts, draining sinuses, communicating sinus tracts, and less commonly comedones.^20,21 The skin can appear erythematous, cyanotic, or dull red.²¹ Most of the lesions are found on the face, particularly on the forehead, cheeks, nose, and chin,²¹ but lesions on the chest and back have been documented in adult patients.²⁰ In an examination of prior case series, most patients were otherwise healthy. There are case reports documenting rosacea fulminans in teenagers,²⁰ but the youngest patient recorded was an otherwise healthy 3-year-old girl who developed a sudden onset of erythematous papules, pustules, cysts, and purulent discharging sinuses on the cheeks that spread to the chin, perioral, and paranasal areas.²¹

Differential Diagnosis

Rosacea is rare in children, so other papulopustular disorders must be ruled out, including acne vulgaris, periorificial/perioral dermatitis, sarcoidosis, systemic lupus erythematosus, steroid-induced rosacea, ataxia telangiectasia, and demodicosis.

Acne vulgaris commonly presents in older adolescents and teenagers with open and closed comedones, inflammatory papules, and pustules.² Intense facial flushing and telangiectasia usually is not seen.

In perioral dermatitis, skin lesions often are clustered around the mouth, nose, and eyes. Typically there are no telangiectases or ocular complications.³ Facial flushing and telangiectases are uncommon, except in steroid-induced perioral dermatitis.²

The cutaneous findings of sarcoidosis include red-brown papules on the face and lips, and patients also may have ocular involvement such as uveitis and iritis.³ However, there are typically other systemic findings such as pulmonary symptoms, weight loss, fatigue, lethargy, fever, and erythema nodosum.^2,3 Chest radiograph findings (eg, bilateral hilar lym-phadenopathy), ophthalmologic examination, and laboratory data (eg, elevated alkaline phosphate and/or elevated angiotensin-converting enzyme) can help confirm or rule out the diagnosis of sarcoidosis.^2,3

Unlike systemic lupus erythematosus, patients with rosacea will have involvement of sun-protected areas of the skin. Patients with systemic lupus erythematosus typically report arthralgia and severe photosensitivity and will have elevated antinuclear antibody titers. Skin biopsies and immunofluorescence can help confirm the diagnosis.³ Importantly, some patients with rosacea will have a positive lupus band test.^22,23

Steroid-induced rosacea typically occurs 2 weeks after discontinuing therapy with topical fluorinated glucocorticosteroids.²⁴ Children present with monomorphic papules, pustules, and telangiectases⁴ on the eyelids and lateral face as opposed to the central face regions.²⁴

Ataxia telangiectasia can present with telangiectases, skin atrophy, café au lait spots, and premature graying.²⁵ A 15-year-old adolescent girl with ataxia telangiectasia presented with granulomatous acne rosacea that improved after 4 weeks of treatment with isotretinoin 0.5 mg/kg daily. The lesions cleared almost completely after 5 months.²⁵

Demodicosis is a disorder of the pilosebaceous units caused by the human Demodex mite.²⁶ It typically involves the periorificial regions in adults and the elderly population. Patients can present with fine, white-yellow, scaly changes of the sebaceous hair follicles, with minimal erythema and inflammation. Papules and pustules also can be present.²⁶

Diagnosis and Histopathology

Because rosacea is rare in children, it is important to thoroughly evaluate other possible diagnoses. The diagnosis of pediatric rosacea is clinical and biopsies are rarely performed. Laboratory tests such as cultures generally are not useful.

Marks and Harcourt-Webster²⁷ reviewed the biopsies of 108 adult patients with rosacea. The biopsies of patients with predominantly erythema and telangiectasia showed evidence of vascular dilatation with a perivascular infiltrate composed predominantly of lymphocytes and 39 specimens that were compared to controls showed more solar elastosis. Biopsies of papular rosacea contained inflammatory infiltrates in the upper and mid dermis composed primarily of lymphocytes and histiocytes. In some patients, neutrophils, plasma cells, and giant cells also were observed. Hair follicle abnormalities were present in 20% of the biopsies, with 19% showing evidence of the Demodex mite. Vascular dilatation also was common. Overall, common findings included lymphohistiocytic infiltrates around the blood vessels of the upper dermis, dilated vessels, edema, elastosis, and disorganization of connective tissue in the upper dermis.

Helm et al²⁸ reviewed histopathologic patterns from 53 patients with granulomatous rosacea. Findings included a mixed lymphohistiocytic infiltrate (predominantly lymphocytic in 40% of patients and predominantly histiocytic with occasional giant cells in 34% of patients), epithelioid granulomas (11% of patients), and epithelioid granulomas with caseation necrosis (11% of patients).

The histopathology of rosacea fulminans is characterized by dense perivascular and periadnexal infiltrates composed of granulocytes, eosinophils, and epithelioid granulomas, as well as panniculitis.²⁰

Treatment and Clinical Outcomes

Certain lifestyle recommendations are integral components of disease management, including avoidance of triggers such as extreme temperatures, hot drinks, spicy food, and topical agents that could be irritating (especially topical corticosteroids).²⁹ Patients should be advised to use daily sunscreen containing physical blockers such as titanium dioxide or zinc oxide. Teenagers should avoid the use of cosmetics and makeup, especially products containing sodium lauryl sulfate, menthol, and camphor. Daily use of emollients can help some patients.²⁹

There are both topical and systemic therapies available for pediatric rosacea; however, most of the data are based on the use of these treatments in the adult population. Patients with mild to moderate disease often can be managed using topical agents. Metronidazole (0.75% cream, 1% gel, or 0.75% lotion) has been studied extensively in adult patients, and when used once daily for 12 weeks, it has been able to control moderate to severe disease.^30,31 In one study conducted in adult patients, topical metronidazole was able to maintain remission in adults who had previously been treated with a combination of oral tetracycline and metronidazole gel.³¹ Sodium sulfacetamide 10%–sulfur 5% (cleanser or lotion) has been successful in adult patients and often is used in combination with other therapies such as topical metronidazole.^32-34 Azelaic acid cream 20%,³⁵ benzoyl peroxide (wash or gel),²⁹ topical clindamycin,³⁶ topical erythromycin,^29,37 tacrolimus ointment 0.1%,³⁸ and tretinoin cream also have been studied in adults.^3,39 Several of these topical agents can cause irritation on application (eg, metronidazole, sulfur-based agents, azelaic acid, benzoyl peroxide, erythromycin, tretinoin).³

The use of systemic treatments in pediatric patients is heavily based on case reports and case series.^2,14,16,40 Therapies have included tetracycline (500 mg twice daily tapered to 250 mg daily),²⁹ minocycline (50–100 mg twice daily), doxycycline (50–100 mg twice daily or 4 times daily), erythromycin (30–50 mg/kg daily), clarithromycin (15 mg/kg twice daily for 4 weeks and then daily for 4 weeks), and azithromycin (5–10 mg/kg daily).³ Tetracycline antibiotics should not be used in children 8 years or younger.

In a case series by Drolet and Paller,² an 11-year-old girl was treated with tetracycline 500 mg (later tapered to 250 mg daily) and metronidazole gel 0.75%, both used twice daily. Previously, she had not responded to topical steroids, tretinoin cream 0.05%, benzoyl peroxide 5%, or systemic prednisone. After 6 weeks of treatment, the pustules and chalazion had resolved and she had only minimal erythema of the skin and conjunctiva. Sixteen months after the start of treatment, a regimen of tetracycline 250 mg daily and metronidazole gel resulted in disease clearance on the face.²

A 9-year-old girl with concurrent systemic lupus erythematosus was treated with tetracycline 250 mg and topical erythromycin 2%, both used twice daily.² After 4 weeks her face was clear. Four months later she developed new telangiectases and topical erythromycin was replaced with topical metronidazole. Eventually the dose of tetracycline was reduced to 250 mg daily.²

An 11-year-old boy with likely granulomatous rosacea was treated with erythromycin 250 mg 4 times daily, alclometasone dipropionate cream 0.05% twice daily, and topical clindamycin twice daily.² Marked improvement was noticed after 3 weeks of treatment. Metronidazole gel 0.75% was added and 3 months later the patient’s face was clear, without evidence of scarring. The dose of erythromycin was later reduced to 500 mg daily, and eventually the patient experienced clearance with the use of metronidazole gel daily.²

In another case series, 4 female patients (age range, 4–12 years) were treated with systemic erythromycin 20 mg/kg daily (ocular involvement only) or doxycycline 2.2 mg/kg daily used in two 12-year-old patients with ocular and cutaneous involvement for at least 12 months. All 4 patients showed considerable improvement within 1 month and remained free of disease throughout a mean follow-up period of 25.5 months.⁴⁰

As evidenced by these case reports, there is a wide array of treatments that have been used for pediatric rosacea. Although there are no formal evidence-based guidelines, there are certain considerations that must be taken into account when choosing treatment plans. Doxycycline and minocycline are known to cause less gastrointestinal upset than tetracycline with similar efficacy.⁴¹ Importantly, the tetracyclines are contraindicated in children younger than 9 years, as they can cause teeth staining and possibly affect skeletal growth.^3,4 When used in older children (age range, 9–12 years), patients must be advised not to take their medication with calcium or antacids.³ Clarithromycin and azithromycin tend to have fewer gastrointestinal side effects than erythromycin. Erythromycin and other macrolides can be used in children of all ages and in patients who are allergic to tetracyclines.³

Children with mild ocular symptoms often can control their disease with bacitracin and topical ocular antibiotics such as erythromycin.^2,15 For patients who require systemic antibiotics, various tetracyclines and macrolides have been used with success.^2,14-16,40

Adults with rosacea fulminans can require treatment with isotretinoin, oral antibiotics, and topical or even systemic corticosteroids.⁴² The 3-year-old girl with rosacea fulminans initially was treated with oral erythromycin (250 mg 4 times daily), oral prednisolone (0.5 mg/kg daily tapered over 2 weeks), fluocinolone acetonide cream 0.025%, and warm compresses with only moderate improvement.²¹ She was then started on oral isotretinoin (0.75 mg/kg daily) and within 4 weeks marked improvement was noted. After 8 weeks, the lesions had disappeared completely with only a few pitted scars remaining. Isotretinoin was continued for 24 weeks. One year after completion of treatment, she was still disease free.²¹

Weston and Morelli¹⁹ recommended the following treatment regimen for children with steroid rosacea: abrupt cessation of topical steroid use (as opposed to gradual withdrawal) and initiation of oral erythromycin stearate (30 mg/kg daily) in 2 daily doses for 4 weeks. Children who were unable to tolerate erythromycin (n=6) were told to use topical clindamycin phosphate twice daily for 4 weeks. Within 3 weeks 22% of patients had resolution, while 86% had resolution within 4 weeks. All of the patients cleared within 8 weeks. Importantly, there was no significant difference in duration of time until clearance between children who used the oral antibiotic or topical antibiotic.¹⁹

Conclusion

We know that the skin of rosacea patients contains higher levels of cathelicidins, which have been implicated in amplifying and contributing to the inflammatory response in several ways. Mast cells, which are a source of cathelicidins, also are increased in the skin of these patients. Children can present with vascular rosacea (characterized by flushing, erythema, and/or telangiectasia), papulopustular rosacea, or ocular rosacea. Common ocular symptoms include blepharitis, conjunctivitis, and recurrent chalazion. It is important to refer pediatric rosacea patients with ocular symptoms to an ophthalmologist to prevent ocular sequelae.

Rosacea is a clinical diagnosis but biopsy can be performed to rule out other diagnoses. Treatment consists of lifestyle modifications such as avoiding known triggers and the use of topical and/or oral agents. Common topical therapies include metronidazole and erythromycin. Systemic antibiotics include tetracycline, doxycycline, minocycline, azithromycin, and erythromycin. Some children are able to taper systemic agents and maintain disease control with topical therapy, while others may need to continue a low-dose antibiotic. Although flares can be controlled within weeks to months, rosacea is a chronic disorder and childhood rosacea tends to persist into adulthood.

Rosacea is a chronic skin disease characterized by flushing, erythema, telangiectasia, papules, and pustules in the central face region.¹ It most often affects middle-aged women (age range, 30–50 years).² Rosacea is rare in the pediatric population, especially before puberty.³ There are 3 subtypes of pediatric rosacea: vascular, papulopustular, and ocular. Phymatous/rhinophymatous rosacea is only seen in the adult population.³ Recommendations for the management of pediatric rosacea heavily rely on data from retrospective chart reviews and case series.

Etiology of Pediatric Rosacea

Rosacea is thought to be a consequence of vasomotor instability in both adults and children. A family history of rosacea is sometimes reported in patients with pediatric rosacea.⁴ Patients often are sensitive to heat, sunlight, topical corticosteroids, spicy foods, hot liquids, and certain soaps and cleansers.^1,3,4 In a review of the literature by Vemuri et al,⁵ the various reported triggers of rosacea include harsh climates that damage the blood vessels and dermal connective tissue, defects in the endothelium and dermal matrix, perivascular inflammation, orally ingested chemicals, changes in the flora of the hair follicles, excessive antimicrobial peptides, and the presence of free radicals. Overall, it is unclear which of these factors are triggers of pediatric rosacea.

The molecular basis of rosacea has been elucidated. It is well known that rosacea patients have higher levels of cathelicidins in the facial skin. Furthermore, they appear to have different processed forms of cathelicidin peptides compared to adults without rosacea, possibly due to changes in posttranslational processing.⁶ One such peptide, cathelicidin LL-37, also has been implicated in atopic dermatitis⁷ and psoriasis.⁸ Its role in rosacea appears to be multifaceted. Cathelicidin LL-37 helps to attract neutrophils, monocytes, and T lymphocytes, and also has antimicrobial properties; therefore, it plays a role in both the innate and adaptive immune systems.⁹ Cathelicidin LL-37 also has been implicated in inducing angiogenesis¹⁰ and suppressing dermal fibroblasts.¹¹

Muto et al¹² found that there is an increased number of mast cells in the dermis of patients with rosacea. Mast cells contribute to vasodilation, angiogenesis, and the recruitment of other inflammatory cells.¹² Importantly, human mast cells are a source of cathelicidins including cathelicidin LL-37; these proteins play a vital role in the antimicrobial capabilities of mast cells.¹³

Clinical Presentation and Comorbidities

Vascular rosacea presents with characteristic flushing and erythema, which lasts more than a few minutes as compared to physiologic erythema,¹ and sometimes telangiectasia is seen.³ The cheeks, chin, and nasolabial folds are most commonly involved.² In papulopustular rosacea, papules and pustules are seen overlying the erythema.^1,3 Open and closed comedones also have been documented in case reports but are not commonly seen.² Pediatric rosacea often begins with flushing of the face and then progresses to the development of papules and pustules.⁴

Ocular rosacea can occur with or without cutaneous findings. In a retrospective study of 20 pediatric patients (aged 1–15 years), 11 (55%) patients had both ocular and cutaneous rosacea, 3 (15%) only had ocular symptoms, and 6 (30%) only had cutaneous symptoms. The most common form of rosacea in this study was papulopustular rosacea.¹⁴ Ocular symptoms often are bilateral¹⁵ and can include blepharitis, conjunctival injection, recurrent chalazion, conjunctivitis,² and less commonly corneal ulceration and scarring.¹⁶ Patients also may report photophobia or a foreign body sensation.¹⁷ Importantly, ocular symptoms often precede the cutaneous symptoms and can delay the diagnosis of rosacea,^14,16,18 as these symptoms often are misdiagnosed as viral or bacterial infections.¹⁵ Fortunately, ocular disease responds well to treatment if diagnosed early.

Weston and Morelli¹⁹ conducted a retrospective study of 106 children (46 males; 60 females) 13 years and younger with steroid rosacea; 29 children were younger than 3 years. A family history of rosacea was present in 20% of participants, and prior use of class 7 steroids was reported in 54%, whereas only 3% had used class 1 topical steroids. Ninety-eight participants had perinasal involvement, 94 had perioral involvement, and 44 had periorbital involvement of the lower eyelids.¹⁹

Rosacea fulminans (also known as pyoderma faciale) is a rare acute-onset eruption typically found in young women in their 20s and 30s.²⁰ Rosacea fulminans is characterized by papules, pustules, nodules, cysts, draining sinuses, communicating sinus tracts, and less commonly comedones.^20,21 The skin can appear erythematous, cyanotic, or dull red.²¹ Most of the lesions are found on the face, particularly on the forehead, cheeks, nose, and chin,²¹ but lesions on the chest and back have been documented in adult patients.²⁰ In an examination of prior case series, most patients were otherwise healthy. There are case reports documenting rosacea fulminans in teenagers,²⁰ but the youngest patient recorded was an otherwise healthy 3-year-old girl who developed a sudden onset of erythematous papules, pustules, cysts, and purulent discharging sinuses on the cheeks that spread to the chin, perioral, and paranasal areas.²¹

Differential Diagnosis

Rosacea is rare in children, so other papulopustular disorders must be ruled out, including acne vulgaris, periorificial/perioral dermatitis, sarcoidosis, systemic lupus erythematosus, steroid-induced rosacea, ataxia telangiectasia, and demodicosis.

Acne vulgaris commonly presents in older adolescents and teenagers with open and closed comedones, inflammatory papules, and pustules.² Intense facial flushing and telangiectasia usually is not seen.

In perioral dermatitis, skin lesions often are clustered around the mouth, nose, and eyes. Typically there are no telangiectases or ocular complications.³ Facial flushing and telangiectases are uncommon, except in steroid-induced perioral dermatitis.²

The cutaneous findings of sarcoidosis include red-brown papules on the face and lips, and patients also may have ocular involvement such as uveitis and iritis.³ However, there are typically other systemic findings such as pulmonary symptoms, weight loss, fatigue, lethargy, fever, and erythema nodosum.^2,3 Chest radiograph findings (eg, bilateral hilar lym-phadenopathy), ophthalmologic examination, and laboratory data (eg, elevated alkaline phosphate and/or elevated angiotensin-converting enzyme) can help confirm or rule out the diagnosis of sarcoidosis.^2,3

Unlike systemic lupus erythematosus, patients with rosacea will have involvement of sun-protected areas of the skin. Patients with systemic lupus erythematosus typically report arthralgia and severe photosensitivity and will have elevated antinuclear antibody titers. Skin biopsies and immunofluorescence can help confirm the diagnosis.³ Importantly, some patients with rosacea will have a positive lupus band test.^22,23

Steroid-induced rosacea typically occurs 2 weeks after discontinuing therapy with topical fluorinated glucocorticosteroids.²⁴ Children present with monomorphic papules, pustules, and telangiectases⁴ on the eyelids and lateral face as opposed to the central face regions.²⁴

Ataxia telangiectasia can present with telangiectases, skin atrophy, café au lait spots, and premature graying.²⁵ A 15-year-old adolescent girl with ataxia telangiectasia presented with granulomatous acne rosacea that improved after 4 weeks of treatment with isotretinoin 0.5 mg/kg daily. The lesions cleared almost completely after 5 months.²⁵

Demodicosis is a disorder of the pilosebaceous units caused by the human Demodex mite.²⁶ It typically involves the periorificial regions in adults and the elderly population. Patients can present with fine, white-yellow, scaly changes of the sebaceous hair follicles, with minimal erythema and inflammation. Papules and pustules also can be present.²⁶

Diagnosis and Histopathology

Because rosacea is rare in children, it is important to thoroughly evaluate other possible diagnoses. The diagnosis of pediatric rosacea is clinical and biopsies are rarely performed. Laboratory tests such as cultures generally are not useful.

Marks and Harcourt-Webster²⁷ reviewed the biopsies of 108 adult patients with rosacea. The biopsies of patients with predominantly erythema and telangiectasia showed evidence of vascular dilatation with a perivascular infiltrate composed predominantly of lymphocytes and 39 specimens that were compared to controls showed more solar elastosis. Biopsies of papular rosacea contained inflammatory infiltrates in the upper and mid dermis composed primarily of lymphocytes and histiocytes. In some patients, neutrophils, plasma cells, and giant cells also were observed. Hair follicle abnormalities were present in 20% of the biopsies, with 19% showing evidence of the Demodex mite. Vascular dilatation also was common. Overall, common findings included lymphohistiocytic infiltrates around the blood vessels of the upper dermis, dilated vessels, edema, elastosis, and disorganization of connective tissue in the upper dermis.

Helm et al²⁸ reviewed histopathologic patterns from 53 patients with granulomatous rosacea. Findings included a mixed lymphohistiocytic infiltrate (predominantly lymphocytic in 40% of patients and predominantly histiocytic with occasional giant cells in 34% of patients), epithelioid granulomas (11% of patients), and epithelioid granulomas with caseation necrosis (11% of patients).

The histopathology of rosacea fulminans is characterized by dense perivascular and periadnexal infiltrates composed of granulocytes, eosinophils, and epithelioid granulomas, as well as panniculitis.²⁰

Treatment and Clinical Outcomes

Certain lifestyle recommendations are integral components of disease management, including avoidance of triggers such as extreme temperatures, hot drinks, spicy food, and topical agents that could be irritating (especially topical corticosteroids).²⁹ Patients should be advised to use daily sunscreen containing physical blockers such as titanium dioxide or zinc oxide. Teenagers should avoid the use of cosmetics and makeup, especially products containing sodium lauryl sulfate, menthol, and camphor. Daily use of emollients can help some patients.²⁹

There are both topical and systemic therapies available for pediatric rosacea; however, most of the data are based on the use of these treatments in the adult population. Patients with mild to moderate disease often can be managed using topical agents. Metronidazole (0.75% cream, 1% gel, or 0.75% lotion) has been studied extensively in adult patients, and when used once daily for 12 weeks, it has been able to control moderate to severe disease.^30,31 In one study conducted in adult patients, topical metronidazole was able to maintain remission in adults who had previously been treated with a combination of oral tetracycline and metronidazole gel.³¹ Sodium sulfacetamide 10%–sulfur 5% (cleanser or lotion) has been successful in adult patients and often is used in combination with other therapies such as topical metronidazole.^32-34 Azelaic acid cream 20%,³⁵ benzoyl peroxide (wash or gel),²⁹ topical clindamycin,³⁶ topical erythromycin,^29,37 tacrolimus ointment 0.1%,³⁸ and tretinoin cream also have been studied in adults.^3,39 Several of these topical agents can cause irritation on application (eg, metronidazole, sulfur-based agents, azelaic acid, benzoyl peroxide, erythromycin, tretinoin).³

The use of systemic treatments in pediatric patients is heavily based on case reports and case series.^2,14,16,40 Therapies have included tetracycline (500 mg twice daily tapered to 250 mg daily),²⁹ minocycline (50–100 mg twice daily), doxycycline (50–100 mg twice daily or 4 times daily), erythromycin (30–50 mg/kg daily), clarithromycin (15 mg/kg twice daily for 4 weeks and then daily for 4 weeks), and azithromycin (5–10 mg/kg daily).³ Tetracycline antibiotics should not be used in children 8 years or younger.

In a case series by Drolet and Paller,² an 11-year-old girl was treated with tetracycline 500 mg (later tapered to 250 mg daily) and metronidazole gel 0.75%, both used twice daily. Previously, she had not responded to topical steroids, tretinoin cream 0.05%, benzoyl peroxide 5%, or systemic prednisone. After 6 weeks of treatment, the pustules and chalazion had resolved and she had only minimal erythema of the skin and conjunctiva. Sixteen months after the start of treatment, a regimen of tetracycline 250 mg daily and metronidazole gel resulted in disease clearance on the face.²

A 9-year-old girl with concurrent systemic lupus erythematosus was treated with tetracycline 250 mg and topical erythromycin 2%, both used twice daily.² After 4 weeks her face was clear. Four months later she developed new telangiectases and topical erythromycin was replaced with topical metronidazole. Eventually the dose of tetracycline was reduced to 250 mg daily.²

An 11-year-old boy with likely granulomatous rosacea was treated with erythromycin 250 mg 4 times daily, alclometasone dipropionate cream 0.05% twice daily, and topical clindamycin twice daily.² Marked improvement was noticed after 3 weeks of treatment. Metronidazole gel 0.75% was added and 3 months later the patient’s face was clear, without evidence of scarring. The dose of erythromycin was later reduced to 500 mg daily, and eventually the patient experienced clearance with the use of metronidazole gel daily.²

In another case series, 4 female patients (age range, 4–12 years) were treated with systemic erythromycin 20 mg/kg daily (ocular involvement only) or doxycycline 2.2 mg/kg daily used in two 12-year-old patients with ocular and cutaneous involvement for at least 12 months. All 4 patients showed considerable improvement within 1 month and remained free of disease throughout a mean follow-up period of 25.5 months.⁴⁰

As evidenced by these case reports, there is a wide array of treatments that have been used for pediatric rosacea. Although there are no formal evidence-based guidelines, there are certain considerations that must be taken into account when choosing treatment plans. Doxycycline and minocycline are known to cause less gastrointestinal upset than tetracycline with similar efficacy.⁴¹ Importantly, the tetracyclines are contraindicated in children younger than 9 years, as they can cause teeth staining and possibly affect skeletal growth.^3,4 When used in older children (age range, 9–12 years), patients must be advised not to take their medication with calcium or antacids.³ Clarithromycin and azithromycin tend to have fewer gastrointestinal side effects than erythromycin. Erythromycin and other macrolides can be used in children of all ages and in patients who are allergic to tetracyclines.³

Children with mild ocular symptoms often can control their disease with bacitracin and topical ocular antibiotics such as erythromycin.^2,15 For patients who require systemic antibiotics, various tetracyclines and macrolides have been used with success.^2,14-16,40

Adults with rosacea fulminans can require treatment with isotretinoin, oral antibiotics, and topical or even systemic corticosteroids.⁴² The 3-year-old girl with rosacea fulminans initially was treated with oral erythromycin (250 mg 4 times daily), oral prednisolone (0.5 mg/kg daily tapered over 2 weeks), fluocinolone acetonide cream 0.025%, and warm compresses with only moderate improvement.²¹ She was then started on oral isotretinoin (0.75 mg/kg daily) and within 4 weeks marked improvement was noted. After 8 weeks, the lesions had disappeared completely with only a few pitted scars remaining. Isotretinoin was continued for 24 weeks. One year after completion of treatment, she was still disease free.²¹

Weston and Morelli¹⁹ recommended the following treatment regimen for children with steroid rosacea: abrupt cessation of topical steroid use (as opposed to gradual withdrawal) and initiation of oral erythromycin stearate (30 mg/kg daily) in 2 daily doses for 4 weeks. Children who were unable to tolerate erythromycin (n=6) were told to use topical clindamycin phosphate twice daily for 4 weeks. Within 3 weeks 22% of patients had resolution, while 86% had resolution within 4 weeks. All of the patients cleared within 8 weeks. Importantly, there was no significant difference in duration of time until clearance between children who used the oral antibiotic or topical antibiotic.¹⁹

Conclusion

We know that the skin of rosacea patients contains higher levels of cathelicidins, which have been implicated in amplifying and contributing to the inflammatory response in several ways. Mast cells, which are a source of cathelicidins, also are increased in the skin of these patients. Children can present with vascular rosacea (characterized by flushing, erythema, and/or telangiectasia), papulopustular rosacea, or ocular rosacea. Common ocular symptoms include blepharitis, conjunctivitis, and recurrent chalazion. It is important to refer pediatric rosacea patients with ocular symptoms to an ophthalmologist to prevent ocular sequelae.

Rosacea is a clinical diagnosis but biopsy can be performed to rule out other diagnoses. Treatment consists of lifestyle modifications such as avoiding known triggers and the use of topical and/or oral agents. Common topical therapies include metronidazole and erythromycin. Systemic antibiotics include tetracycline, doxycycline, minocycline, azithromycin, and erythromycin. Some children are able to taper systemic agents and maintain disease control with topical therapy, while others may need to continue a low-dose antibiotic. Although flares can be controlled within weeks to months, rosacea is a chronic disorder and childhood rosacea tends to persist into adulthood.

Consider melanoma-associated leukoderma (MAL) as a possible diagnosis in patients presenting with atypical vitiligo-like skin depigmentation that is refractory to standard treatment, advised the authors of a series of seven such cases.

In a research letter published online in the British Journal of Dermatology, Dr. H.E. Teulings and colleagues from the department of dermatology and the Netherlands Institute for Pigment Disorders at the University of Amsterdam, presented a retrospective analysis of seven patients diagnosed with MAL from 2009-2014, who had been initially diagnosed with nonsegmental vitiligo.

The authors defined MAL as “depigmentation that developed within 1 year before the detection of a primary melanoma or within 3 years before the detection of melanoma metastases with an unknown primary tumour.”

The five women and two men were white and were older (aged 45 to 72 years). They had experienced a sudden onset of highly progressive hypo- and depigmentation, which the authors described as often consisting of “round, patchy, confetti-like lesions” measuring 4-5 mm in diameter; most were scattered symmetrically over the trunk, extremities, and/or face (Br J Dermatol. 2016 Jun 7. doi: 10.1111/bjd.14790).

The authors noted that this presentation was unlike typical vitiligo, “which is often bilaterally distributed in an acrofacial pattern, or scattered symmetrically over the entire body with a predilection for extensor surfaces with a relatively early onset in life and a slowly evolving disease course over time.”

The lesions were also generally resistant to topical steroids and UV phototherapy, and six of the seven patients had no family history of vitiligo. The patients were either diagnosed with a primary melanoma at first presentation or were later diagnosed with metastatic melanoma. The majority responded well to immunotherapy, although one patient died.

“In conclusion, although MAL only constitutes a small percentage of patients presenting with vitiligo-like depigmentation, awareness of this phenomenon and correct diagnosis of these patients is crucial to limit further melanoma treatment delay,” the authors wrote. “Many dermatologists are not aware of the diagnosis MAL and may easily diagnose and treat these patients as having nonsegmental vitiligo, thereby overlooking the underlying (metastatic) melanoma,” they added.

Dr. Teulings is supported by a grant from the Dutch Cancer Society. The authors had no conflicts of interest to declare.

Consider melanoma-associated leukoderma (MAL) as a possible diagnosis in patients presenting with atypical vitiligo-like skin depigmentation that is refractory to standard treatment, advised the authors of a series of seven such cases.

In a research letter published online in the British Journal of Dermatology, Dr. H.E. Teulings and colleagues from the department of dermatology and the Netherlands Institute for Pigment Disorders at the University of Amsterdam, presented a retrospective analysis of seven patients diagnosed with MAL from 2009-2014, who had been initially diagnosed with nonsegmental vitiligo.

The authors defined MAL as “depigmentation that developed within 1 year before the detection of a primary melanoma or within 3 years before the detection of melanoma metastases with an unknown primary tumour.”

The five women and two men were white and were older (aged 45 to 72 years). They had experienced a sudden onset of highly progressive hypo- and depigmentation, which the authors described as often consisting of “round, patchy, confetti-like lesions” measuring 4-5 mm in diameter; most were scattered symmetrically over the trunk, extremities, and/or face (Br J Dermatol. 2016 Jun 7. doi: 10.1111/bjd.14790).

The authors noted that this presentation was unlike typical vitiligo, “which is often bilaterally distributed in an acrofacial pattern, or scattered symmetrically over the entire body with a predilection for extensor surfaces with a relatively early onset in life and a slowly evolving disease course over time.”

The lesions were also generally resistant to topical steroids and UV phototherapy, and six of the seven patients had no family history of vitiligo. The patients were either diagnosed with a primary melanoma at first presentation or were later diagnosed with metastatic melanoma. The majority responded well to immunotherapy, although one patient died.

“In conclusion, although MAL only constitutes a small percentage of patients presenting with vitiligo-like depigmentation, awareness of this phenomenon and correct diagnosis of these patients is crucial to limit further melanoma treatment delay,” the authors wrote. “Many dermatologists are not aware of the diagnosis MAL and may easily diagnose and treat these patients as having nonsegmental vitiligo, thereby overlooking the underlying (metastatic) melanoma,” they added.

Dr. Teulings is supported by a grant from the Dutch Cancer Society. The authors had no conflicts of interest to declare.

Consider melanoma-associated leukoderma (MAL) as a possible diagnosis in patients presenting with atypical vitiligo-like skin depigmentation that is refractory to standard treatment, advised the authors of a series of seven such cases.

In a research letter published online in the British Journal of Dermatology, Dr. H.E. Teulings and colleagues from the department of dermatology and the Netherlands Institute for Pigment Disorders at the University of Amsterdam, presented a retrospective analysis of seven patients diagnosed with MAL from 2009-2014, who had been initially diagnosed with nonsegmental vitiligo.

The authors defined MAL as “depigmentation that developed within 1 year before the detection of a primary melanoma or within 3 years before the detection of melanoma metastases with an unknown primary tumour.”

The five women and two men were white and were older (aged 45 to 72 years). They had experienced a sudden onset of highly progressive hypo- and depigmentation, which the authors described as often consisting of “round, patchy, confetti-like lesions” measuring 4-5 mm in diameter; most were scattered symmetrically over the trunk, extremities, and/or face (Br J Dermatol. 2016 Jun 7. doi: 10.1111/bjd.14790).

The authors noted that this presentation was unlike typical vitiligo, “which is often bilaterally distributed in an acrofacial pattern, or scattered symmetrically over the entire body with a predilection for extensor surfaces with a relatively early onset in life and a slowly evolving disease course over time.”

The lesions were also generally resistant to topical steroids and UV phototherapy, and six of the seven patients had no family history of vitiligo. The patients were either diagnosed with a primary melanoma at first presentation or were later diagnosed with metastatic melanoma. The majority responded well to immunotherapy, although one patient died.

“In conclusion, although MAL only constitutes a small percentage of patients presenting with vitiligo-like depigmentation, awareness of this phenomenon and correct diagnosis of these patients is crucial to limit further melanoma treatment delay,” the authors wrote. “Many dermatologists are not aware of the diagnosis MAL and may easily diagnose and treat these patients as having nonsegmental vitiligo, thereby overlooking the underlying (metastatic) melanoma,” they added.

Dr. Teulings is supported by a grant from the Dutch Cancer Society. The authors had no conflicts of interest to declare.