Two studies show a link between industry payments by drug manufacturers to physicians and doctors’ prescribing patterns for certain medications.

Artfoliophoto/Thinkstock

In the first study, lead author Taeho Greg Rhee, PhD, of the University of Connecticut, Farmington, and colleagues analyzed Centers for Medicare & Medicaid Services Part D data and Open Payments data for general payments from industry to physicians associated with gabapentinoids.

Specifically, investigators examined data for three brand name products: Gralise (Assertio) and Horizant (Arbor), both of which are extended release formulas approved for the treatment of seizure disorders and postherpetic neuralgia, and Lyrica (Pfizer), which is approved for treatment of seizure disorders, postherpetic neuralgia, neuropathic pain, and fibromyalgia. To evaluate prescribing patterns, researchers estimated physician prescribing as the physician’s proportion of prescription days filled for the three brand-name gabapentinoids in aggregate of all gabapentinoid prescription days filled.

Between 2014 and 2016, manufacturers of the three brand-name gabapentinoids made approximately 510,000 general payments ($11.5 million) to 51,005 physicians, according to Dr. Rhee and colleagues. The doctors represented 14% of physicians who prescribed any gabapentinoid product under Part D during the same time period.

Among physicians who prescribed any gabapentinoid, generic forms of Gralise (gabapentin; 87%) and Lyrica (pregabalin; 12%) were most frequently prescribed. However, physicians receiving payments from industry were more likely to prescribe the three brand-name gabapentinoids than they were gabapentin (JAMA Intern Med. 2019 July 8. doi: 10.1001/jamainternmed.2019.1082).

Generalist physicians received the majority of payments (62%) payments totaling about $4 million, followed by about $7 million for pain medication specialists and $1 million for other physicians.

The majority of payments were for food and beverages, gifts, or educational materials. In addition, industry payments were most commonly paid to physicians in the southern and eastern regions of the United States.

Among physicians who prescribed gabapentinoids, industry payment was associated with a higher likelihood of prescribing brand-name products than generic gabapentin and that such prescribing patterns increase Medicare spending. Data show that brand name gabapentinoids typically cost account for nearly $2,500 in mean Medicare spending per beneficiary in 2016, compared with less than $20 for a 1-month supply of gabapentin, authors noted.

In the second study, Rishad Khan, MD, of the University of Toronto and colleagues examined the association between industry payments to physicians and Medicare spending on adalimumab (Humira; AbbVie) and certolizumab (Cimzia; Union Chimique Belge), both of which are approved for Crohn’s disease and numerous other indications. Investigators analyzed CMS Part D data and Open Payments data linked to the prescribing of adalimumab and certolizumab. Payments were considered relevant if a gastroenterologist received them from a drug manufacturer the year that the medication was prescribed.

From 2014 to 2016, drug makers made more than $10 million in payments to gastroenterologists prescribing adalimumab or certolizumab, the study found. Investigators found that for every $1 in physician payments, there was a $3.16 increase in spending for adalimumab and a $4.72 increase for certolizumab (JAMA Intern Med. 2019 July 8. doi: 10.1001/jamainternmed.2019.0999).

For adalimumab, payments totaled $5.5 million for speaking and consulting, $4.9 million for food, travel,and lodging expenses, and $13,000 for education. For certolizumab, payments totaled $180,000 for speaking and consulting, $117,000 for food, travel,and lodging expenses, and $60,000 for education.

Dr. Khan and associates concluded that the findings suggest a significant association between industry payments by drug manufacturers to physicians and Medicare spending.

[email protected]

Two studies show a link between industry payments by drug manufacturers to physicians and doctors’ prescribing patterns for certain medications.

Artfoliophoto/Thinkstock

In the first study, lead author Taeho Greg Rhee, PhD, of the University of Connecticut, Farmington, and colleagues analyzed Centers for Medicare & Medicaid Services Part D data and Open Payments data for general payments from industry to physicians associated with gabapentinoids.

Specifically, investigators examined data for three brand name products: Gralise (Assertio) and Horizant (Arbor), both of which are extended release formulas approved for the treatment of seizure disorders and postherpetic neuralgia, and Lyrica (Pfizer), which is approved for treatment of seizure disorders, postherpetic neuralgia, neuropathic pain, and fibromyalgia. To evaluate prescribing patterns, researchers estimated physician prescribing as the physician’s proportion of prescription days filled for the three brand-name gabapentinoids in aggregate of all gabapentinoid prescription days filled.

Between 2014 and 2016, manufacturers of the three brand-name gabapentinoids made approximately 510,000 general payments ($11.5 million) to 51,005 physicians, according to Dr. Rhee and colleagues. The doctors represented 14% of physicians who prescribed any gabapentinoid product under Part D during the same time period.

Among physicians who prescribed any gabapentinoid, generic forms of Gralise (gabapentin; 87%) and Lyrica (pregabalin; 12%) were most frequently prescribed. However, physicians receiving payments from industry were more likely to prescribe the three brand-name gabapentinoids than they were gabapentin (JAMA Intern Med. 2019 July 8. doi: 10.1001/jamainternmed.2019.1082).

Generalist physicians received the majority of payments (62%) payments totaling about $4 million, followed by about $7 million for pain medication specialists and $1 million for other physicians.

The majority of payments were for food and beverages, gifts, or educational materials. In addition, industry payments were most commonly paid to physicians in the southern and eastern regions of the United States.

Among physicians who prescribed gabapentinoids, industry payment was associated with a higher likelihood of prescribing brand-name products than generic gabapentin and that such prescribing patterns increase Medicare spending. Data show that brand name gabapentinoids typically cost account for nearly $2,500 in mean Medicare spending per beneficiary in 2016, compared with less than $20 for a 1-month supply of gabapentin, authors noted.

In the second study, Rishad Khan, MD, of the University of Toronto and colleagues examined the association between industry payments to physicians and Medicare spending on adalimumab (Humira; AbbVie) and certolizumab (Cimzia; Union Chimique Belge), both of which are approved for Crohn’s disease and numerous other indications. Investigators analyzed CMS Part D data and Open Payments data linked to the prescribing of adalimumab and certolizumab. Payments were considered relevant if a gastroenterologist received them from a drug manufacturer the year that the medication was prescribed.

From 2014 to 2016, drug makers made more than $10 million in payments to gastroenterologists prescribing adalimumab or certolizumab, the study found. Investigators found that for every $1 in physician payments, there was a $3.16 increase in spending for adalimumab and a $4.72 increase for certolizumab (JAMA Intern Med. 2019 July 8. doi: 10.1001/jamainternmed.2019.0999).

For adalimumab, payments totaled $5.5 million for speaking and consulting, $4.9 million for food, travel,and lodging expenses, and $13,000 for education. For certolizumab, payments totaled $180,000 for speaking and consulting, $117,000 for food, travel,and lodging expenses, and $60,000 for education.

Dr. Khan and associates concluded that the findings suggest a significant association between industry payments by drug manufacturers to physicians and Medicare spending.

[email protected]

Two studies show a link between industry payments by drug manufacturers to physicians and doctors’ prescribing patterns for certain medications.

Artfoliophoto/Thinkstock

In the first study, lead author Taeho Greg Rhee, PhD, of the University of Connecticut, Farmington, and colleagues analyzed Centers for Medicare & Medicaid Services Part D data and Open Payments data for general payments from industry to physicians associated with gabapentinoids.

Specifically, investigators examined data for three brand name products: Gralise (Assertio) and Horizant (Arbor), both of which are extended release formulas approved for the treatment of seizure disorders and postherpetic neuralgia, and Lyrica (Pfizer), which is approved for treatment of seizure disorders, postherpetic neuralgia, neuropathic pain, and fibromyalgia. To evaluate prescribing patterns, researchers estimated physician prescribing as the physician’s proportion of prescription days filled for the three brand-name gabapentinoids in aggregate of all gabapentinoid prescription days filled.

Between 2014 and 2016, manufacturers of the three brand-name gabapentinoids made approximately 510,000 general payments ($11.5 million) to 51,005 physicians, according to Dr. Rhee and colleagues. The doctors represented 14% of physicians who prescribed any gabapentinoid product under Part D during the same time period.

Among physicians who prescribed any gabapentinoid, generic forms of Gralise (gabapentin; 87%) and Lyrica (pregabalin; 12%) were most frequently prescribed. However, physicians receiving payments from industry were more likely to prescribe the three brand-name gabapentinoids than they were gabapentin (JAMA Intern Med. 2019 July 8. doi: 10.1001/jamainternmed.2019.1082).

Generalist physicians received the majority of payments (62%) payments totaling about $4 million, followed by about $7 million for pain medication specialists and $1 million for other physicians.

The majority of payments were for food and beverages, gifts, or educational materials. In addition, industry payments were most commonly paid to physicians in the southern and eastern regions of the United States.

Among physicians who prescribed gabapentinoids, industry payment was associated with a higher likelihood of prescribing brand-name products than generic gabapentin and that such prescribing patterns increase Medicare spending. Data show that brand name gabapentinoids typically cost account for nearly $2,500 in mean Medicare spending per beneficiary in 2016, compared with less than $20 for a 1-month supply of gabapentin, authors noted.

In the second study, Rishad Khan, MD, of the University of Toronto and colleagues examined the association between industry payments to physicians and Medicare spending on adalimumab (Humira; AbbVie) and certolizumab (Cimzia; Union Chimique Belge), both of which are approved for Crohn’s disease and numerous other indications. Investigators analyzed CMS Part D data and Open Payments data linked to the prescribing of adalimumab and certolizumab. Payments were considered relevant if a gastroenterologist received them from a drug manufacturer the year that the medication was prescribed.

From 2014 to 2016, drug makers made more than $10 million in payments to gastroenterologists prescribing adalimumab or certolizumab, the study found. Investigators found that for every $1 in physician payments, there was a $3.16 increase in spending for adalimumab and a $4.72 increase for certolizumab (JAMA Intern Med. 2019 July 8. doi: 10.1001/jamainternmed.2019.0999).

For adalimumab, payments totaled $5.5 million for speaking and consulting, $4.9 million for food, travel,and lodging expenses, and $13,000 for education. For certolizumab, payments totaled $180,000 for speaking and consulting, $117,000 for food, travel,and lodging expenses, and $60,000 for education.

Dr. Khan and associates concluded that the findings suggest a significant association between industry payments by drug manufacturers to physicians and Medicare spending.

[email protected]

Two doses of recombinant zoster vaccine significantly reduced incidence of herpes zoster in adults who had undergone autologous hematopoietic stem cell transplantation (HSCT), results of a randomized, placebo-controlled trial indicate.

The incidence of herpes zoster was 30 per 1,000 person-years for patients who received the adjuvanted recombinant zoster vaccine (Shingrix) versus 94 per 1,000 person-years for those who received placebo, according to study results.

Recombinant zoster vaccine induced humoral and cellular responses that were strong and occurring at a rate higher than what was seen in the placebo group, said senior author Keith M. Sullivan, MD, of Duke University Medical Center, Durham, N.C., and coauthors, who reported findings on behalf of the Zoster Efficacy Study in Patients Undergoing HSCT (ZOE-HSCT) Study Group.

“The vaccinations were generally well tolerated, and most symptoms were mild and transient and did not substantially deter participants from receiving their second dose,” Dr. Sullivan and colleagues wrote in JAMA.

The risk of herpes zoster is increased for 2-3 years after autologous HSCT because of diminished T-cell immunity, according to the authors.

“Antiviral prophylaxis is commonly administered to patients after HSCT to prevent such complications, but the efficacy depends on adherence to treatment,” they said.

While vaccines could provide long-term protection, immunocompromised individuals receiving live attenuated vaccine would be at increased risk of varicella caused by spread of the vaccine strain, they added.

There have been a few encouraging recent studies of non-live vaccines in this setting, including one large phase 3 trial of a heat-inactivated varicella-zoster virus vaccine that showed patients undergoing autologous HSCT had a 63.8% estimated efficacy in preventing herpes zoster, investigators from that study said in The Lancet (2018 May 26;391[10135]:2116-27).

A phase 1/2a study of the adjuvanted recombinant zoster vaccine in patients undergoing HSCT demonstrated strong humoral and cell-mediated immunity responses, which provided the rationale for studying the vaccine further in the randomized ZOE-HSCT study, according to Dr. Sullivan and coauthors.

Their study included a total of 1,846 adults who had undergone autologous HSCT. They were randomized to receive two doses of the recombinant zoster vaccine, the first at 50-70 days after the procedure and the second 1-2 months later.

Herpes zoster cases were seen in 49 and 136 individuals in the vaccine and placebo groups, respectively, which resulted in overall incidences of 30 and 94 per 1,000 person-years.

The incidence rate ratio of a first episode of herpes zoster was 0.36 for individuals receiving at least one dose, which authors said was equivalent to a vaccine efficacy of 63.7%.

That efficacy rate is “very similar” to the estimated efficacy reported for the heat-inactivated varicella-zoster virus vaccine reported in The Lancet, said Dr. Sullivan and coauthors.

However, the heat-inactivated vaccine achieved that level of protection with a four-dose schedule, including one dose given prior to autologous HSCT.

“An advantage of the short 2-dose posttransplantation schedule is that more patients might complete the vaccination program,” they said in a discussion of the results, noting that 94.7% of the recombinant zoster vaccine recipients completed two doses, compared with 81.9% of recipients who received the heat-inactivated herpes zoster vaccine in the previous report.

The study was funded and sponsored by GlaxoSmithKline Biologicals SA. Dr. Sullivan reported disclosures related to GlaxoSmithKline (GSK), Kiadis Pharmaceutical, Roche Genentech, and the National Institute of Allergy and Infectious Diseases. Coauthors provided disclosures related to GSK, AbbVie, Roche, Gilead, Janssen, Pharmacyclics, Morphosys, Helsinn, Celgene, and others.

SOURCE: Bastidas A et al. JAMA. 2019 July 9. doi: 10.1001/jama.2019.9053.

Two doses of recombinant zoster vaccine significantly reduced incidence of herpes zoster in adults who had undergone autologous hematopoietic stem cell transplantation (HSCT), results of a randomized, placebo-controlled trial indicate.

The incidence of herpes zoster was 30 per 1,000 person-years for patients who received the adjuvanted recombinant zoster vaccine (Shingrix) versus 94 per 1,000 person-years for those who received placebo, according to study results.

Recombinant zoster vaccine induced humoral and cellular responses that were strong and occurring at a rate higher than what was seen in the placebo group, said senior author Keith M. Sullivan, MD, of Duke University Medical Center, Durham, N.C., and coauthors, who reported findings on behalf of the Zoster Efficacy Study in Patients Undergoing HSCT (ZOE-HSCT) Study Group.

“The vaccinations were generally well tolerated, and most symptoms were mild and transient and did not substantially deter participants from receiving their second dose,” Dr. Sullivan and colleagues wrote in JAMA.

The risk of herpes zoster is increased for 2-3 years after autologous HSCT because of diminished T-cell immunity, according to the authors.

“Antiviral prophylaxis is commonly administered to patients after HSCT to prevent such complications, but the efficacy depends on adherence to treatment,” they said.

While vaccines could provide long-term protection, immunocompromised individuals receiving live attenuated vaccine would be at increased risk of varicella caused by spread of the vaccine strain, they added.

There have been a few encouraging recent studies of non-live vaccines in this setting, including one large phase 3 trial of a heat-inactivated varicella-zoster virus vaccine that showed patients undergoing autologous HSCT had a 63.8% estimated efficacy in preventing herpes zoster, investigators from that study said in The Lancet (2018 May 26;391[10135]:2116-27).

A phase 1/2a study of the adjuvanted recombinant zoster vaccine in patients undergoing HSCT demonstrated strong humoral and cell-mediated immunity responses, which provided the rationale for studying the vaccine further in the randomized ZOE-HSCT study, according to Dr. Sullivan and coauthors.

Their study included a total of 1,846 adults who had undergone autologous HSCT. They were randomized to receive two doses of the recombinant zoster vaccine, the first at 50-70 days after the procedure and the second 1-2 months later.

Herpes zoster cases were seen in 49 and 136 individuals in the vaccine and placebo groups, respectively, which resulted in overall incidences of 30 and 94 per 1,000 person-years.

The incidence rate ratio of a first episode of herpes zoster was 0.36 for individuals receiving at least one dose, which authors said was equivalent to a vaccine efficacy of 63.7%.

That efficacy rate is “very similar” to the estimated efficacy reported for the heat-inactivated varicella-zoster virus vaccine reported in The Lancet, said Dr. Sullivan and coauthors.

However, the heat-inactivated vaccine achieved that level of protection with a four-dose schedule, including one dose given prior to autologous HSCT.

“An advantage of the short 2-dose posttransplantation schedule is that more patients might complete the vaccination program,” they said in a discussion of the results, noting that 94.7% of the recombinant zoster vaccine recipients completed two doses, compared with 81.9% of recipients who received the heat-inactivated herpes zoster vaccine in the previous report.

The study was funded and sponsored by GlaxoSmithKline Biologicals SA. Dr. Sullivan reported disclosures related to GlaxoSmithKline (GSK), Kiadis Pharmaceutical, Roche Genentech, and the National Institute of Allergy and Infectious Diseases. Coauthors provided disclosures related to GSK, AbbVie, Roche, Gilead, Janssen, Pharmacyclics, Morphosys, Helsinn, Celgene, and others.

SOURCE: Bastidas A et al. JAMA. 2019 July 9. doi: 10.1001/jama.2019.9053.

Two doses of recombinant zoster vaccine significantly reduced incidence of herpes zoster in adults who had undergone autologous hematopoietic stem cell transplantation (HSCT), results of a randomized, placebo-controlled trial indicate.

The incidence of herpes zoster was 30 per 1,000 person-years for patients who received the adjuvanted recombinant zoster vaccine (Shingrix) versus 94 per 1,000 person-years for those who received placebo, according to study results.

Recombinant zoster vaccine induced humoral and cellular responses that were strong and occurring at a rate higher than what was seen in the placebo group, said senior author Keith M. Sullivan, MD, of Duke University Medical Center, Durham, N.C., and coauthors, who reported findings on behalf of the Zoster Efficacy Study in Patients Undergoing HSCT (ZOE-HSCT) Study Group.

“The vaccinations were generally well tolerated, and most symptoms were mild and transient and did not substantially deter participants from receiving their second dose,” Dr. Sullivan and colleagues wrote in JAMA.

The risk of herpes zoster is increased for 2-3 years after autologous HSCT because of diminished T-cell immunity, according to the authors.

“Antiviral prophylaxis is commonly administered to patients after HSCT to prevent such complications, but the efficacy depends on adherence to treatment,” they said.

While vaccines could provide long-term protection, immunocompromised individuals receiving live attenuated vaccine would be at increased risk of varicella caused by spread of the vaccine strain, they added.

There have been a few encouraging recent studies of non-live vaccines in this setting, including one large phase 3 trial of a heat-inactivated varicella-zoster virus vaccine that showed patients undergoing autologous HSCT had a 63.8% estimated efficacy in preventing herpes zoster, investigators from that study said in The Lancet (2018 May 26;391[10135]:2116-27).

A phase 1/2a study of the adjuvanted recombinant zoster vaccine in patients undergoing HSCT demonstrated strong humoral and cell-mediated immunity responses, which provided the rationale for studying the vaccine further in the randomized ZOE-HSCT study, according to Dr. Sullivan and coauthors.

Their study included a total of 1,846 adults who had undergone autologous HSCT. They were randomized to receive two doses of the recombinant zoster vaccine, the first at 50-70 days after the procedure and the second 1-2 months later.

Herpes zoster cases were seen in 49 and 136 individuals in the vaccine and placebo groups, respectively, which resulted in overall incidences of 30 and 94 per 1,000 person-years.

The incidence rate ratio of a first episode of herpes zoster was 0.36 for individuals receiving at least one dose, which authors said was equivalent to a vaccine efficacy of 63.7%.

That efficacy rate is “very similar” to the estimated efficacy reported for the heat-inactivated varicella-zoster virus vaccine reported in The Lancet, said Dr. Sullivan and coauthors.

However, the heat-inactivated vaccine achieved that level of protection with a four-dose schedule, including one dose given prior to autologous HSCT.

“An advantage of the short 2-dose posttransplantation schedule is that more patients might complete the vaccination program,” they said in a discussion of the results, noting that 94.7% of the recombinant zoster vaccine recipients completed two doses, compared with 81.9% of recipients who received the heat-inactivated herpes zoster vaccine in the previous report.

The study was funded and sponsored by GlaxoSmithKline Biologicals SA. Dr. Sullivan reported disclosures related to GlaxoSmithKline (GSK), Kiadis Pharmaceutical, Roche Genentech, and the National Institute of Allergy and Infectious Diseases. Coauthors provided disclosures related to GSK, AbbVie, Roche, Gilead, Janssen, Pharmacyclics, Morphosys, Helsinn, Celgene, and others.

SOURCE: Bastidas A et al. JAMA. 2019 July 9. doi: 10.1001/jama.2019.9053.

SAN ANTONIO – Continuous positive airway pressure (CPAP) adherence varies by age, sex, and date of setup, results from an analysis of national data showed.

Courtesy Dr. Krishna Sundar

However, whether the sources of variability stem from patient factors such as disease severity and socioeconomic status, provider factors, environmental factors, or selection biases in those who are diagnosed with obstructive sleep apnea and treated with CPAP remains to be understood, lead study author Sanjay R. Patel, MD, said at the annual meeting of the Associated Professional Sleep Societies.

In 2015, the American Academy of Sleep Medicine (AASM) endorsed CPAP adherence as a process measure, and the Centers for Medicare and Medicaid Services has used CPAP adherence as an outcome measure to limit long-term coverage of the therapy. It defines CPAP adherence as 4 or more hours of use on greater than 70% of nights in a consecutive 30-day period within the first 90 days. “Strengths of CPAP adherence as an outcome measure include the fact that it is easy to measure and it predicts improvement in sleepiness, quality of life, and blood pressure control,” said Dr. Patel, who directs the University of Pittsburgh’s Center for Sleep and Cardiovascular Outcomes Research. “One issue as to whether we should use CPAP adherence as an outcome-based quality of care measure is, does variability reflect performance at the provider and/or health care system?”

In an effort to describe CPAP adherence rates in general clinical practice as well as sources of variability, Dr. Patel and colleagues evaluated telemonitoring data maintained by Philips Respironics. The study population consisted of 714,270 patients initiated on CPAP therapy between November 2015 and August 2018 who had at least one usage session of CPAP or APAP.

Overall, 90-day adherence to CPAP was 72.5%. Age, sex, and state of residence were all significantly associated with adherence rates (P less than .05). Specifically, adherence rates ranged from 54.8% among those 18-30 years of age to 79.1% among those 61-70 years of age. “There was a plateauing of adherence rates among those in their 70s, and men tended to have a higher adherence level than women across all age groups (73.3% vs. 71.4%, respectively),” he said. “Also, people who got started on CPAP in January had a higher level of adherence than people who got started in May. The differences are relatively small compared to the large age differences, but there was a consistent trend.”


When the researchers carried out age- and sex-adjusted analyses, they observed that adherence rates were lowest in the Northeast and Southwest and highest in the Upper Midwest and Mountain West. Adherence rates ranged from 50.8% in the District of Columbia and 60.5% in New York up to 81.2% in Idaho and 81.9% in South Dakota.

“The question is, is this variability explained by quality measures?” Dr. Patel asked. “We tried to answer this question by seeing whether the variability in adherence by location correlated with other metrics of health care quality.” To accomplish this, they used Dartmouth Atlas, a project that uses Medicare data to understand drivers of health care spending and quality. To understand geographic variability in CPAP adherence, they mapped ZIP codes onto hospital referral regions (HRRs), which are regional health care markets for tertiary medical care. Each HRR has at least one hospital that performs major cardiovascular procedures and neurosurgery. ZIP codes were mapped to 306 HRRs where the majority of residents get their tertiary care.

The researchers observed that Medicare enrollees who saw a primary care physician in the past 12 months had higher rates of adherence, compared with those who did not. “Twenty-three percent of the variance in CPAP adherence across the country can be explained by this measure of having a primary care doctor,” Dr. Patel said. In addition, patients who received care from HRRs located in the middle of the United States had high adherence rates. Top performers were facilities located in Madison, Wis.; Wausau, Wis.; Dubuque, Iowa; and Bloomington, Ill. Poor performers included facilities located in the boroughs of Manhattan and the Bronx, in New York; Muskegon, Mich.; Miami; and Buffalo, N.Y.

“Some of the geographical variability may be due to patient factors such as race, income, and education level,” Dr. Patel said. “That will need to be appropriately addressed in developing a quality of care measure. Nevertheless, some of the geographic variability appears to be related to health care system and provider factors. This variability could be potentially reduced through implementation of a CPAP adherence quality outcome measure.”

Dr. Patel disclosed that he has received grant/research support from Bayer Pharmaceuticals and Philips Respironics, and has served as a consultant to the American Academy of Sleep Medicine.

[email protected]

SOURCE: Patel SR et al. SLEEP 2019, Abstract 0513.

SAN ANTONIO – Continuous positive airway pressure (CPAP) adherence varies by age, sex, and date of setup, results from an analysis of national data showed.

Courtesy Dr. Krishna Sundar

However, whether the sources of variability stem from patient factors such as disease severity and socioeconomic status, provider factors, environmental factors, or selection biases in those who are diagnosed with obstructive sleep apnea and treated with CPAP remains to be understood, lead study author Sanjay R. Patel, MD, said at the annual meeting of the Associated Professional Sleep Societies.

In 2015, the American Academy of Sleep Medicine (AASM) endorsed CPAP adherence as a process measure, and the Centers for Medicare and Medicaid Services has used CPAP adherence as an outcome measure to limit long-term coverage of the therapy. It defines CPAP adherence as 4 or more hours of use on greater than 70% of nights in a consecutive 30-day period within the first 90 days. “Strengths of CPAP adherence as an outcome measure include the fact that it is easy to measure and it predicts improvement in sleepiness, quality of life, and blood pressure control,” said Dr. Patel, who directs the University of Pittsburgh’s Center for Sleep and Cardiovascular Outcomes Research. “One issue as to whether we should use CPAP adherence as an outcome-based quality of care measure is, does variability reflect performance at the provider and/or health care system?”

In an effort to describe CPAP adherence rates in general clinical practice as well as sources of variability, Dr. Patel and colleagues evaluated telemonitoring data maintained by Philips Respironics. The study population consisted of 714,270 patients initiated on CPAP therapy between November 2015 and August 2018 who had at least one usage session of CPAP or APAP.

Overall, 90-day adherence to CPAP was 72.5%. Age, sex, and state of residence were all significantly associated with adherence rates (P less than .05). Specifically, adherence rates ranged from 54.8% among those 18-30 years of age to 79.1% among those 61-70 years of age. “There was a plateauing of adherence rates among those in their 70s, and men tended to have a higher adherence level than women across all age groups (73.3% vs. 71.4%, respectively),” he said. “Also, people who got started on CPAP in January had a higher level of adherence than people who got started in May. The differences are relatively small compared to the large age differences, but there was a consistent trend.”


When the researchers carried out age- and sex-adjusted analyses, they observed that adherence rates were lowest in the Northeast and Southwest and highest in the Upper Midwest and Mountain West. Adherence rates ranged from 50.8% in the District of Columbia and 60.5% in New York up to 81.2% in Idaho and 81.9% in South Dakota.

“The question is, is this variability explained by quality measures?” Dr. Patel asked. “We tried to answer this question by seeing whether the variability in adherence by location correlated with other metrics of health care quality.” To accomplish this, they used Dartmouth Atlas, a project that uses Medicare data to understand drivers of health care spending and quality. To understand geographic variability in CPAP adherence, they mapped ZIP codes onto hospital referral regions (HRRs), which are regional health care markets for tertiary medical care. Each HRR has at least one hospital that performs major cardiovascular procedures and neurosurgery. ZIP codes were mapped to 306 HRRs where the majority of residents get their tertiary care.

The researchers observed that Medicare enrollees who saw a primary care physician in the past 12 months had higher rates of adherence, compared with those who did not. “Twenty-three percent of the variance in CPAP adherence across the country can be explained by this measure of having a primary care doctor,” Dr. Patel said. In addition, patients who received care from HRRs located in the middle of the United States had high adherence rates. Top performers were facilities located in Madison, Wis.; Wausau, Wis.; Dubuque, Iowa; and Bloomington, Ill. Poor performers included facilities located in the boroughs of Manhattan and the Bronx, in New York; Muskegon, Mich.; Miami; and Buffalo, N.Y.

“Some of the geographical variability may be due to patient factors such as race, income, and education level,” Dr. Patel said. “That will need to be appropriately addressed in developing a quality of care measure. Nevertheless, some of the geographic variability appears to be related to health care system and provider factors. This variability could be potentially reduced through implementation of a CPAP adherence quality outcome measure.”

Dr. Patel disclosed that he has received grant/research support from Bayer Pharmaceuticals and Philips Respironics, and has served as a consultant to the American Academy of Sleep Medicine.

[email protected]

SOURCE: Patel SR et al. SLEEP 2019, Abstract 0513.

SAN ANTONIO – Continuous positive airway pressure (CPAP) adherence varies by age, sex, and date of setup, results from an analysis of national data showed.

Courtesy Dr. Krishna Sundar

However, whether the sources of variability stem from patient factors such as disease severity and socioeconomic status, provider factors, environmental factors, or selection biases in those who are diagnosed with obstructive sleep apnea and treated with CPAP remains to be understood, lead study author Sanjay R. Patel, MD, said at the annual meeting of the Associated Professional Sleep Societies.

In 2015, the American Academy of Sleep Medicine (AASM) endorsed CPAP adherence as a process measure, and the Centers for Medicare and Medicaid Services has used CPAP adherence as an outcome measure to limit long-term coverage of the therapy. It defines CPAP adherence as 4 or more hours of use on greater than 70% of nights in a consecutive 30-day period within the first 90 days. “Strengths of CPAP adherence as an outcome measure include the fact that it is easy to measure and it predicts improvement in sleepiness, quality of life, and blood pressure control,” said Dr. Patel, who directs the University of Pittsburgh’s Center for Sleep and Cardiovascular Outcomes Research. “One issue as to whether we should use CPAP adherence as an outcome-based quality of care measure is, does variability reflect performance at the provider and/or health care system?”

In an effort to describe CPAP adherence rates in general clinical practice as well as sources of variability, Dr. Patel and colleagues evaluated telemonitoring data maintained by Philips Respironics. The study population consisted of 714,270 patients initiated on CPAP therapy between November 2015 and August 2018 who had at least one usage session of CPAP or APAP.

Overall, 90-day adherence to CPAP was 72.5%. Age, sex, and state of residence were all significantly associated with adherence rates (P less than .05). Specifically, adherence rates ranged from 54.8% among those 18-30 years of age to 79.1% among those 61-70 years of age. “There was a plateauing of adherence rates among those in their 70s, and men tended to have a higher adherence level than women across all age groups (73.3% vs. 71.4%, respectively),” he said. “Also, people who got started on CPAP in January had a higher level of adherence than people who got started in May. The differences are relatively small compared to the large age differences, but there was a consistent trend.”


When the researchers carried out age- and sex-adjusted analyses, they observed that adherence rates were lowest in the Northeast and Southwest and highest in the Upper Midwest and Mountain West. Adherence rates ranged from 50.8% in the District of Columbia and 60.5% in New York up to 81.2% in Idaho and 81.9% in South Dakota.

“The question is, is this variability explained by quality measures?” Dr. Patel asked. “We tried to answer this question by seeing whether the variability in adherence by location correlated with other metrics of health care quality.” To accomplish this, they used Dartmouth Atlas, a project that uses Medicare data to understand drivers of health care spending and quality. To understand geographic variability in CPAP adherence, they mapped ZIP codes onto hospital referral regions (HRRs), which are regional health care markets for tertiary medical care. Each HRR has at least one hospital that performs major cardiovascular procedures and neurosurgery. ZIP codes were mapped to 306 HRRs where the majority of residents get their tertiary care.

The researchers observed that Medicare enrollees who saw a primary care physician in the past 12 months had higher rates of adherence, compared with those who did not. “Twenty-three percent of the variance in CPAP adherence across the country can be explained by this measure of having a primary care doctor,” Dr. Patel said. In addition, patients who received care from HRRs located in the middle of the United States had high adherence rates. Top performers were facilities located in Madison, Wis.; Wausau, Wis.; Dubuque, Iowa; and Bloomington, Ill. Poor performers included facilities located in the boroughs of Manhattan and the Bronx, in New York; Muskegon, Mich.; Miami; and Buffalo, N.Y.

“Some of the geographical variability may be due to patient factors such as race, income, and education level,” Dr. Patel said. “That will need to be appropriately addressed in developing a quality of care measure. Nevertheless, some of the geographic variability appears to be related to health care system and provider factors. This variability could be potentially reduced through implementation of a CPAP adherence quality outcome measure.”

Dr. Patel disclosed that he has received grant/research support from Bayer Pharmaceuticals and Philips Respironics, and has served as a consultant to the American Academy of Sleep Medicine.

[email protected]

SOURCE: Patel SR et al. SLEEP 2019, Abstract 0513.

The Indian Health Service (IHS) and the Cherokee Nation Health Service are launching a new pilot project to help “accelerate progress” toward ending the HIV epidemic in native communities.

The project, which will investigate the most effective prevention strategies and share the findings locally, is part of the initiative Ending the HIV Epidemic: A Plan for America. That plan focuses prevention and treatment efforts on 48 counties and 7 southern states with a higher proportion of HIV diagnosis in rural areas. The Cherokee Nation is in Oklahoma, which has the highest American Indian population among the 7 southern states.

Recent data show new HIV infections at the lowest level yet, but progress in prevention has slowed, in part due to new threats such as the opioid crisis: 10% of new HIV infections are among injectable-drug users.

The Cherokee Nation’s proven track record in hepatitis C prevention and treatment makes it a valuable partner in the project. Half of its health services patients have been screened, and among the 3.2% testing positive, 90% have been cured. The pilot project will use a similar model, IHS says. Current statistics show that 35% of Cherokee National patients using the tribe’s health centers have been screened for HIV, with < 1% testing positive. Of the patients diagnosed with HIV, 90% are receiving care and 90% of those are virally suppressed. The pilot project is aimed at boosting the screening numbers.

The pilot is one of several HHS efforts to jumpstart key activities in select communities using resources from the Minority HIV/AIDS fund. The CDC also is launching projects in select communities.

“Improved health care over multiple generations is our top priority,” said Cherokee Nation Principal Chief Bill John Baker. “If we can collaborate with our federal partners at IHS to raise awareness, increase education, and actively work to prevent new cases of HIV, then we will be creating a healthier future for northeast Oklahoma.”

The Indian Health Service (IHS) and the Cherokee Nation Health Service are launching a new pilot project to help “accelerate progress” toward ending the HIV epidemic in native communities.

The project, which will investigate the most effective prevention strategies and share the findings locally, is part of the initiative Ending the HIV Epidemic: A Plan for America. That plan focuses prevention and treatment efforts on 48 counties and 7 southern states with a higher proportion of HIV diagnosis in rural areas. The Cherokee Nation is in Oklahoma, which has the highest American Indian population among the 7 southern states.

Recent data show new HIV infections at the lowest level yet, but progress in prevention has slowed, in part due to new threats such as the opioid crisis: 10% of new HIV infections are among injectable-drug users.

The Cherokee Nation’s proven track record in hepatitis C prevention and treatment makes it a valuable partner in the project. Half of its health services patients have been screened, and among the 3.2% testing positive, 90% have been cured. The pilot project will use a similar model, IHS says. Current statistics show that 35% of Cherokee National patients using the tribe’s health centers have been screened for HIV, with < 1% testing positive. Of the patients diagnosed with HIV, 90% are receiving care and 90% of those are virally suppressed. The pilot project is aimed at boosting the screening numbers.

The pilot is one of several HHS efforts to jumpstart key activities in select communities using resources from the Minority HIV/AIDS fund. The CDC also is launching projects in select communities.

“Improved health care over multiple generations is our top priority,” said Cherokee Nation Principal Chief Bill John Baker. “If we can collaborate with our federal partners at IHS to raise awareness, increase education, and actively work to prevent new cases of HIV, then we will be creating a healthier future for northeast Oklahoma.”

The Indian Health Service (IHS) and the Cherokee Nation Health Service are launching a new pilot project to help “accelerate progress” toward ending the HIV epidemic in native communities.

The project, which will investigate the most effective prevention strategies and share the findings locally, is part of the initiative Ending the HIV Epidemic: A Plan for America. That plan focuses prevention and treatment efforts on 48 counties and 7 southern states with a higher proportion of HIV diagnosis in rural areas. The Cherokee Nation is in Oklahoma, which has the highest American Indian population among the 7 southern states.

Recent data show new HIV infections at the lowest level yet, but progress in prevention has slowed, in part due to new threats such as the opioid crisis: 10% of new HIV infections are among injectable-drug users.

The Cherokee Nation’s proven track record in hepatitis C prevention and treatment makes it a valuable partner in the project. Half of its health services patients have been screened, and among the 3.2% testing positive, 90% have been cured. The pilot project will use a similar model, IHS says. Current statistics show that 35% of Cherokee National patients using the tribe’s health centers have been screened for HIV, with < 1% testing positive. Of the patients diagnosed with HIV, 90% are receiving care and 90% of those are virally suppressed. The pilot project is aimed at boosting the screening numbers.

The pilot is one of several HHS efforts to jumpstart key activities in select communities using resources from the Minority HIV/AIDS fund. The CDC also is launching projects in select communities.

“Improved health care over multiple generations is our top priority,” said Cherokee Nation Principal Chief Bill John Baker. “If we can collaborate with our federal partners at IHS to raise awareness, increase education, and actively work to prevent new cases of HIV, then we will be creating a healthier future for northeast Oklahoma.”

MILAN – Get ready for a “boxing match” over the next few years, as two treatment categories duke it out for their place in the therapeutic armamentarium for atopic dermatitis (AD), Thomas Bieber, MD, PhD, said in an oral presentation at the World Congress of Dermatology.

“In one corner of the ring you will have the biologics, and in the other corner of the ring, you will have the Janus kinase (JAK) inhibitors and some other small molecules,” said Dr. Bieber, medical director of dermatology and allergy, at University Hospital Bonn, Germany.

There will be no winner-take-all scenario, since AD is a heterogeneous disease for which a variety of treatments will be needed, Dr. Bieber noted. However, he said, there are clear differences in mode of action, safety, mode of application, price, and more that will be important as dermatologists weigh the choice of biologics versus JAK inhibitors for a specific patient.

“Currently, dupilumab is the only one that is on the market (in the European Union) and this molecule is really a revolution for us,” Dr. Bieber said at the meeting. “But we will see in the next years, many, many other molecules coming up.”

Beyond dupilumab (Dupixent), the interleukin-4 (IL-4) receptor alpha antagonist approved by the Food and Drug Administration in 2017, biologics under development include tralokinumab, lebrikizumab, and nemolizumab, among others. Development on the small molecule side includes agents such as ZPL-389, a histamine H4 receptor agonist, but is dominated by JAK inhibitors such as baricitinib(Olumiant), approved by the FDA in 2018 for rheumatoid arthritis; upadacitinib; and abrocitinib, according to Dr. Bieber.

There are advantages and disadvantages to each class of molecule, he said. For example, JAK inhibitors act very rapidly to control itch and improve exacerbations, while biologics are “much slower” and provide delayed control of inflammation, he said. In terms of safety, by contrast, biologics probably offer a “better” benefit-to-risk ratio, with no risk for drug-drug interactions and no monitoring needed, while JAK inhibitors appear to have a “narrow” therapeutic window, with a risk for drug-drug interactions and a need for some monitoring, he said.


JAK inhibitors come in a tablet formulation, which, from the patient perspective, may be more convenient and acceptable compared with repeated injections of biologics every 2 or 4 weeks, Dr. Bieber noted. Another point potentially in favor of JAK inhibitors is price: “I think the current situation tells us clearly that the biologics are the more expensive drugs, while the small molecules typically are much less expensive,” he said.

One theoretical advantage of biologics, he said, is the potential for disease modification, while the disease-modifying potential of JAK inhibitors is unclear, as of yet. “We have not had enough experience with all these molecules in order to understand how we can do that particular job, in terms of switching off the disease,” he said.

In terms of the need for patient stratification in the future, it’s a draw between biologics and JAK inhibitors, Dr. Bieber said. “You will not see any of these drugs doing 100 percent of the job in 100 percent of the patients, so to me, currently from my understanding of this disease, there is no one-size-fits-all molecule.”

Toward that end, machine learning and artificial intelligence may aid in evaluating large amounts of data to better understand AD phenotypes. “That’s really something that is a particular kind of challenge in the next years, in order to improve at-the-end drug development, and the management of our patients,” he concluded.

Dr. Bieber reported disclosures related to LEO Pharmaceuticals, Regeneron, and Sanofi.

MILAN – Get ready for a “boxing match” over the next few years, as two treatment categories duke it out for their place in the therapeutic armamentarium for atopic dermatitis (AD), Thomas Bieber, MD, PhD, said in an oral presentation at the World Congress of Dermatology.

“In one corner of the ring you will have the biologics, and in the other corner of the ring, you will have the Janus kinase (JAK) inhibitors and some other small molecules,” said Dr. Bieber, medical director of dermatology and allergy, at University Hospital Bonn, Germany.

There will be no winner-take-all scenario, since AD is a heterogeneous disease for which a variety of treatments will be needed, Dr. Bieber noted. However, he said, there are clear differences in mode of action, safety, mode of application, price, and more that will be important as dermatologists weigh the choice of biologics versus JAK inhibitors for a specific patient.

“Currently, dupilumab is the only one that is on the market (in the European Union) and this molecule is really a revolution for us,” Dr. Bieber said at the meeting. “But we will see in the next years, many, many other molecules coming up.”

Beyond dupilumab (Dupixent), the interleukin-4 (IL-4) receptor alpha antagonist approved by the Food and Drug Administration in 2017, biologics under development include tralokinumab, lebrikizumab, and nemolizumab, among others. Development on the small molecule side includes agents such as ZPL-389, a histamine H4 receptor agonist, but is dominated by JAK inhibitors such as baricitinib(Olumiant), approved by the FDA in 2018 for rheumatoid arthritis; upadacitinib; and abrocitinib, according to Dr. Bieber.

There are advantages and disadvantages to each class of molecule, he said. For example, JAK inhibitors act very rapidly to control itch and improve exacerbations, while biologics are “much slower” and provide delayed control of inflammation, he said. In terms of safety, by contrast, biologics probably offer a “better” benefit-to-risk ratio, with no risk for drug-drug interactions and no monitoring needed, while JAK inhibitors appear to have a “narrow” therapeutic window, with a risk for drug-drug interactions and a need for some monitoring, he said.


JAK inhibitors come in a tablet formulation, which, from the patient perspective, may be more convenient and acceptable compared with repeated injections of biologics every 2 or 4 weeks, Dr. Bieber noted. Another point potentially in favor of JAK inhibitors is price: “I think the current situation tells us clearly that the biologics are the more expensive drugs, while the small molecules typically are much less expensive,” he said.

One theoretical advantage of biologics, he said, is the potential for disease modification, while the disease-modifying potential of JAK inhibitors is unclear, as of yet. “We have not had enough experience with all these molecules in order to understand how we can do that particular job, in terms of switching off the disease,” he said.

In terms of the need for patient stratification in the future, it’s a draw between biologics and JAK inhibitors, Dr. Bieber said. “You will not see any of these drugs doing 100 percent of the job in 100 percent of the patients, so to me, currently from my understanding of this disease, there is no one-size-fits-all molecule.”

Toward that end, machine learning and artificial intelligence may aid in evaluating large amounts of data to better understand AD phenotypes. “That’s really something that is a particular kind of challenge in the next years, in order to improve at-the-end drug development, and the management of our patients,” he concluded.

Dr. Bieber reported disclosures related to LEO Pharmaceuticals, Regeneron, and Sanofi.

MILAN – Get ready for a “boxing match” over the next few years, as two treatment categories duke it out for their place in the therapeutic armamentarium for atopic dermatitis (AD), Thomas Bieber, MD, PhD, said in an oral presentation at the World Congress of Dermatology.

“In one corner of the ring you will have the biologics, and in the other corner of the ring, you will have the Janus kinase (JAK) inhibitors and some other small molecules,” said Dr. Bieber, medical director of dermatology and allergy, at University Hospital Bonn, Germany.

There will be no winner-take-all scenario, since AD is a heterogeneous disease for which a variety of treatments will be needed, Dr. Bieber noted. However, he said, there are clear differences in mode of action, safety, mode of application, price, and more that will be important as dermatologists weigh the choice of biologics versus JAK inhibitors for a specific patient.

“Currently, dupilumab is the only one that is on the market (in the European Union) and this molecule is really a revolution for us,” Dr. Bieber said at the meeting. “But we will see in the next years, many, many other molecules coming up.”

Beyond dupilumab (Dupixent), the interleukin-4 (IL-4) receptor alpha antagonist approved by the Food and Drug Administration in 2017, biologics under development include tralokinumab, lebrikizumab, and nemolizumab, among others. Development on the small molecule side includes agents such as ZPL-389, a histamine H4 receptor agonist, but is dominated by JAK inhibitors such as baricitinib(Olumiant), approved by the FDA in 2018 for rheumatoid arthritis; upadacitinib; and abrocitinib, according to Dr. Bieber.

There are advantages and disadvantages to each class of molecule, he said. For example, JAK inhibitors act very rapidly to control itch and improve exacerbations, while biologics are “much slower” and provide delayed control of inflammation, he said. In terms of safety, by contrast, biologics probably offer a “better” benefit-to-risk ratio, with no risk for drug-drug interactions and no monitoring needed, while JAK inhibitors appear to have a “narrow” therapeutic window, with a risk for drug-drug interactions and a need for some monitoring, he said.


JAK inhibitors come in a tablet formulation, which, from the patient perspective, may be more convenient and acceptable compared with repeated injections of biologics every 2 or 4 weeks, Dr. Bieber noted. Another point potentially in favor of JAK inhibitors is price: “I think the current situation tells us clearly that the biologics are the more expensive drugs, while the small molecules typically are much less expensive,” he said.

One theoretical advantage of biologics, he said, is the potential for disease modification, while the disease-modifying potential of JAK inhibitors is unclear, as of yet. “We have not had enough experience with all these molecules in order to understand how we can do that particular job, in terms of switching off the disease,” he said.

In terms of the need for patient stratification in the future, it’s a draw between biologics and JAK inhibitors, Dr. Bieber said. “You will not see any of these drugs doing 100 percent of the job in 100 percent of the patients, so to me, currently from my understanding of this disease, there is no one-size-fits-all molecule.”

Toward that end, machine learning and artificial intelligence may aid in evaluating large amounts of data to better understand AD phenotypes. “That’s really something that is a particular kind of challenge in the next years, in order to improve at-the-end drug development, and the management of our patients,” he concluded.

Dr. Bieber reported disclosures related to LEO Pharmaceuticals, Regeneron, and Sanofi.

Practice Gap

Habit-tic nail deformity results from repetitive manipulation of the cuticle and/or proximal nail fold. It most commonly affects one or both thumbnails and presents with a characteristic longitudinal midline furrow with parallel transverse ridges in the nail plate. Complications may include permanent onychodystrophy, frictional melanonychia, and infections. Treatment is challenging, as diagnosis first requires patient insight to the cause of symptoms. Therapeutic options include nonpharmacologic techniques (eg, occlusion of the nails to prevent trauma, cyanoacrylate adhesives, cognitive behavioral therapy) and pharmacologic techniques (eg, N-acetyl cysteine, selective serotonin reuptake inhibitors, tricyclic antidepressants, antipsychotics), with limited supporting data and potential adverse effects.¹

The Technique

Benzethonium chloride solution 0.2% is an antiseptic that creates a polymeric layer that binds to the skin. It normally is used to treat small skin erosions and prevent blisters. In patients with habit-tic nail deformity, we recommend once-daily application of benzethonium chloride to the proximal nail fold, thereby artificially recreating the cuticle and forming a sustainable barrier from trauma (Figure, A). Patients should be reminded not to manipulate the cuticle and/or nail fold during treatment. In one 36-year-old man with habit tic nail deformity, we saw clear nail growth after 4 months of treatment (Figure, B).

Practice Implications

Successful treatment of habit-tic nail deformity requires patients to have some insight into their behavior. The benzethonium chloride serves as a reminder for patients to stop picking as an unfamiliar artificial barrier and reminds them to substitute the picking behavior for another more positive behavior. Therefore, benzethonium chloride may be offered to patients as a novel therapy to both protect the cuticle and alter behavior in patients with habit-tic nail deformity, as it can be difficult to treat with few available therapies.

Allergic contact dermatitis to benzethonium chloride is a potential side effect and patients should be cautioned prior to treatment; however, it is extremely rare with 6 cases reported to date based on a PubMed search of articles indexed for MEDLINE using the terms allergic contact dermatitis and benzethonium chloride,² and much rarer than contact allergy to cyanoacrylates.

Practice Gap

Habit-tic nail deformity results from repetitive manipulation of the cuticle and/or proximal nail fold. It most commonly affects one or both thumbnails and presents with a characteristic longitudinal midline furrow with parallel transverse ridges in the nail plate. Complications may include permanent onychodystrophy, frictional melanonychia, and infections. Treatment is challenging, as diagnosis first requires patient insight to the cause of symptoms. Therapeutic options include nonpharmacologic techniques (eg, occlusion of the nails to prevent trauma, cyanoacrylate adhesives, cognitive behavioral therapy) and pharmacologic techniques (eg, N-acetyl cysteine, selective serotonin reuptake inhibitors, tricyclic antidepressants, antipsychotics), with limited supporting data and potential adverse effects.¹

The Technique

Benzethonium chloride solution 0.2% is an antiseptic that creates a polymeric layer that binds to the skin. It normally is used to treat small skin erosions and prevent blisters. In patients with habit-tic nail deformity, we recommend once-daily application of benzethonium chloride to the proximal nail fold, thereby artificially recreating the cuticle and forming a sustainable barrier from trauma (Figure, A). Patients should be reminded not to manipulate the cuticle and/or nail fold during treatment. In one 36-year-old man with habit tic nail deformity, we saw clear nail growth after 4 months of treatment (Figure, B).

Practice Implications

Successful treatment of habit-tic nail deformity requires patients to have some insight into their behavior. The benzethonium chloride serves as a reminder for patients to stop picking as an unfamiliar artificial barrier and reminds them to substitute the picking behavior for another more positive behavior. Therefore, benzethonium chloride may be offered to patients as a novel therapy to both protect the cuticle and alter behavior in patients with habit-tic nail deformity, as it can be difficult to treat with few available therapies.

Allergic contact dermatitis to benzethonium chloride is a potential side effect and patients should be cautioned prior to treatment; however, it is extremely rare with 6 cases reported to date based on a PubMed search of articles indexed for MEDLINE using the terms allergic contact dermatitis and benzethonium chloride,² and much rarer than contact allergy to cyanoacrylates.

Practice Gap

Habit-tic nail deformity results from repetitive manipulation of the cuticle and/or proximal nail fold. It most commonly affects one or both thumbnails and presents with a characteristic longitudinal midline furrow with parallel transverse ridges in the nail plate. Complications may include permanent onychodystrophy, frictional melanonychia, and infections. Treatment is challenging, as diagnosis first requires patient insight to the cause of symptoms. Therapeutic options include nonpharmacologic techniques (eg, occlusion of the nails to prevent trauma, cyanoacrylate adhesives, cognitive behavioral therapy) and pharmacologic techniques (eg, N-acetyl cysteine, selective serotonin reuptake inhibitors, tricyclic antidepressants, antipsychotics), with limited supporting data and potential adverse effects.¹

The Technique

Benzethonium chloride solution 0.2% is an antiseptic that creates a polymeric layer that binds to the skin. It normally is used to treat small skin erosions and prevent blisters. In patients with habit-tic nail deformity, we recommend once-daily application of benzethonium chloride to the proximal nail fold, thereby artificially recreating the cuticle and forming a sustainable barrier from trauma (Figure, A). Patients should be reminded not to manipulate the cuticle and/or nail fold during treatment. In one 36-year-old man with habit tic nail deformity, we saw clear nail growth after 4 months of treatment (Figure, B).

Practice Implications

Successful treatment of habit-tic nail deformity requires patients to have some insight into their behavior. The benzethonium chloride serves as a reminder for patients to stop picking as an unfamiliar artificial barrier and reminds them to substitute the picking behavior for another more positive behavior. Therefore, benzethonium chloride may be offered to patients as a novel therapy to both protect the cuticle and alter behavior in patients with habit-tic nail deformity, as it can be difficult to treat with few available therapies.

Allergic contact dermatitis to benzethonium chloride is a potential side effect and patients should be cautioned prior to treatment; however, it is extremely rare with 6 cases reported to date based on a PubMed search of articles indexed for MEDLINE using the terms allergic contact dermatitis and benzethonium chloride,² and much rarer than contact allergy to cyanoacrylates.

Case Report

A 32-year-old woman presented to the dermatology clinic with a tender lump overlying the right maxilla of 6 weeks’ duration. The lesion developed acutely 1 to 2 months after the patient began using an at-home microdermabrasion device, which she routinely cleaned with tap water. The physical examination was notable for a 1.5-cm, soft, superficially indurated plaque on the right cheek without associated lymphadenopathy (Figure).

A punch biopsy revealed underlying necrotic fat. Computed tomography of the neck showed 20-mm skin thickening overlying the right zygomatic arch, with minimal adjacent subcutaneous soft tissue stranding and reactive lymph nodes. Further histologic examination of the biopsy specimen revealed inflamed granulation tissue with granulomatous inflammation.

Acid-fast bacterial culture was positive. Subsequent speciation revealed the causal agent to be multidrug-resistant Mycobacterium abscessus. The patient was initially treated with trimethoprim-sulfamethoxazole, which was switched to a combination of doxycycline and levofloxacin a few days later after initial culture returned. The following week, after the specific microorganism was confirmed with specific sensitivity, treatment was changed to intravenous (IV) tigecycline and amikacin. This regimen was continued for 2 more months through a peripherally inserted central catheter, then discontinued after complete resolution of the skin lesion.

Comment

Mycobacterial Infection
Nontuberculous mycobacteria were not identified as human pathogens until the 1950s. They are known to cause skin disease, lymphadenitis, skeletal infection, pulmonary disease, and disseminated infection, with pulmonary disease being the most common clinical form overall.¹Mycobacterium abscessus is a member of a more specific group known as rapidly growing nontuberculous mycobacteria, which also includes Mycobacterium fortuitum and Mycobacterium chelonae.² Commonly found in water, soil, and dust, M abscessus causes skin and soft tissue infection after skin injury by inoculation, minor trauma, or surgery.^2-4 An increased rate of infections recently has been attributed to an increase in cosmetic procedures such as tattooing, liposuction, mesotherapy, pedicures, and body piercing. Mycobacterial infections transmitted through acupuncture also have been documented.^5,6

Causes of Skin and Soft Tissue Infections
Skin and soft tissue infections due to rapidly growing mycobacteria often are associated with systemic comorbidities that cause immunosuppression and with immunosuppressive medications.⁷ Our patient did not have a preexisting comorbidity and did not take any long-term medication. When multiple lesions have been reported, patients were more likely to either have a systemic comorbidity or be taking immunosuppressive medication compared to patients with a single lesion. A history of penetrating trauma or an invasive surgical procedure has been reported more often in patients with a single lesion.⁷

Our patient had a solitary lesion on the face; improper sterile technique while using an at-home microdermabrasion device was thought to be the cause of infection. Although generally considered a minimally abrasive treatment modality, microdermabrasion caused enough trauma to create a nidus of infection in our patient.

Presentation
Cutaneous infection from rapidly growing mycobacteria can manifest as a nonhealing ulceration, subcutaneous abscess, draining sinus, or subcutaneous fluctuant or firm nodules. Erythema may be found in association with ulcers or chronic drainage from a surgical wound.^2,7

Histopathologic appearance varies, depending on the evolution of the disease and host immunologic status. Tuberculoid, palisading, and sarcoidlike granulomas; a diffuse infiltrate of histiocytic foamy cells; acute and chronic panniculitis; nonspecific chronic inflammation; cutaneous abscess; suppurative granuloma; and necrotizing folliculitis all can be seen.⁸ Immunosuppressed patients are less likely to form granulomas.⁶ Diagnosis often is delayed because acid-fast bacterial culture is not typically performed on skin biopsy specimens or surgical wound infections.⁷ Fortunately, a high index of suspicion in our patient’s case allowed for prompt diagnosis and expeditious management.

Management
Mycobacterium abscessus tends to be resistant to conventional antituberculous medications; overall, it is considered a highly drug-resistant pathogen that is difficult to treat.^9,10 Treatment usually requires 3 to 6 months of therapy, with oral clarithromycin considered the first-line agent for localized infection.⁵ Because cases of clarithromycin resistance have been reported in patients with M chelonae infection, caution is warranted when deciding between monotherapy or combination therapy.⁷ Multidrug resistance often necessitates prolonged IV therapy. Amikacin is the mostly commonly used IV agent for M abscessus infection. Adverse effects of treatment are common, often leading to a change in or discontinuation of therapy.¹¹

Our patient was initially given trimethoprim-sulfamethoxazole before being switched to doxycycline and levofloxacin prior to final results of susceptibility testing. Ultimately, due to the multidrug-resistant nature of M abscessus, clarithromycin was not a viable option. Therefore, the patient was administered tigecycline and amikacin through a peripherally inserted central catheter until symptoms fully resolved.

Surgery can be an important adjunctive measure for certain patients, especially those with a single lesion.⁷ Our patient did well with medical treatment alone.

Conclusion

Given the difficulty of treating skin and soft tissue infections caused by M abscessus and related mycobacteria, it is worth noting that these infections are increasingly caused by procedures generally considered to be minimally invasive. Microdermabrasion—performed at home in an unsterile environment and not by a trained medical professional—was the causal procedure in this case. An important consideration is whether clinicians can be comfortable with the use of these treatments at home or whether they should be advising patients against at-home treatments that have potentially serious complications.

Case Report

A 32-year-old woman presented to the dermatology clinic with a tender lump overlying the right maxilla of 6 weeks’ duration. The lesion developed acutely 1 to 2 months after the patient began using an at-home microdermabrasion device, which she routinely cleaned with tap water. The physical examination was notable for a 1.5-cm, soft, superficially indurated plaque on the right cheek without associated lymphadenopathy (Figure).

A punch biopsy revealed underlying necrotic fat. Computed tomography of the neck showed 20-mm skin thickening overlying the right zygomatic arch, with minimal adjacent subcutaneous soft tissue stranding and reactive lymph nodes. Further histologic examination of the biopsy specimen revealed inflamed granulation tissue with granulomatous inflammation.

Acid-fast bacterial culture was positive. Subsequent speciation revealed the causal agent to be multidrug-resistant Mycobacterium abscessus. The patient was initially treated with trimethoprim-sulfamethoxazole, which was switched to a combination of doxycycline and levofloxacin a few days later after initial culture returned. The following week, after the specific microorganism was confirmed with specific sensitivity, treatment was changed to intravenous (IV) tigecycline and amikacin. This regimen was continued for 2 more months through a peripherally inserted central catheter, then discontinued after complete resolution of the skin lesion.

Comment

Mycobacterial Infection
Nontuberculous mycobacteria were not identified as human pathogens until the 1950s. They are known to cause skin disease, lymphadenitis, skeletal infection, pulmonary disease, and disseminated infection, with pulmonary disease being the most common clinical form overall.¹Mycobacterium abscessus is a member of a more specific group known as rapidly growing nontuberculous mycobacteria, which also includes Mycobacterium fortuitum and Mycobacterium chelonae.² Commonly found in water, soil, and dust, M abscessus causes skin and soft tissue infection after skin injury by inoculation, minor trauma, or surgery.^2-4 An increased rate of infections recently has been attributed to an increase in cosmetic procedures such as tattooing, liposuction, mesotherapy, pedicures, and body piercing. Mycobacterial infections transmitted through acupuncture also have been documented.^5,6

Causes of Skin and Soft Tissue Infections
Skin and soft tissue infections due to rapidly growing mycobacteria often are associated with systemic comorbidities that cause immunosuppression and with immunosuppressive medications.⁷ Our patient did not have a preexisting comorbidity and did not take any long-term medication. When multiple lesions have been reported, patients were more likely to either have a systemic comorbidity or be taking immunosuppressive medication compared to patients with a single lesion. A history of penetrating trauma or an invasive surgical procedure has been reported more often in patients with a single lesion.⁷

Our patient had a solitary lesion on the face; improper sterile technique while using an at-home microdermabrasion device was thought to be the cause of infection. Although generally considered a minimally abrasive treatment modality, microdermabrasion caused enough trauma to create a nidus of infection in our patient.

Presentation
Cutaneous infection from rapidly growing mycobacteria can manifest as a nonhealing ulceration, subcutaneous abscess, draining sinus, or subcutaneous fluctuant or firm nodules. Erythema may be found in association with ulcers or chronic drainage from a surgical wound.^2,7

Histopathologic appearance varies, depending on the evolution of the disease and host immunologic status. Tuberculoid, palisading, and sarcoidlike granulomas; a diffuse infiltrate of histiocytic foamy cells; acute and chronic panniculitis; nonspecific chronic inflammation; cutaneous abscess; suppurative granuloma; and necrotizing folliculitis all can be seen.⁸ Immunosuppressed patients are less likely to form granulomas.⁶ Diagnosis often is delayed because acid-fast bacterial culture is not typically performed on skin biopsy specimens or surgical wound infections.⁷ Fortunately, a high index of suspicion in our patient’s case allowed for prompt diagnosis and expeditious management.

Management
Mycobacterium abscessus tends to be resistant to conventional antituberculous medications; overall, it is considered a highly drug-resistant pathogen that is difficult to treat.^9,10 Treatment usually requires 3 to 6 months of therapy, with oral clarithromycin considered the first-line agent for localized infection.⁵ Because cases of clarithromycin resistance have been reported in patients with M chelonae infection, caution is warranted when deciding between monotherapy or combination therapy.⁷ Multidrug resistance often necessitates prolonged IV therapy. Amikacin is the mostly commonly used IV agent for M abscessus infection. Adverse effects of treatment are common, often leading to a change in or discontinuation of therapy.¹¹

Our patient was initially given trimethoprim-sulfamethoxazole before being switched to doxycycline and levofloxacin prior to final results of susceptibility testing. Ultimately, due to the multidrug-resistant nature of M abscessus, clarithromycin was not a viable option. Therefore, the patient was administered tigecycline and amikacin through a peripherally inserted central catheter until symptoms fully resolved.

Surgery can be an important adjunctive measure for certain patients, especially those with a single lesion.⁷ Our patient did well with medical treatment alone.

Conclusion

Given the difficulty of treating skin and soft tissue infections caused by M abscessus and related mycobacteria, it is worth noting that these infections are increasingly caused by procedures generally considered to be minimally invasive. Microdermabrasion—performed at home in an unsterile environment and not by a trained medical professional—was the causal procedure in this case. An important consideration is whether clinicians can be comfortable with the use of these treatments at home or whether they should be advising patients against at-home treatments that have potentially serious complications.

Case Report

A 32-year-old woman presented to the dermatology clinic with a tender lump overlying the right maxilla of 6 weeks’ duration. The lesion developed acutely 1 to 2 months after the patient began using an at-home microdermabrasion device, which she routinely cleaned with tap water. The physical examination was notable for a 1.5-cm, soft, superficially indurated plaque on the right cheek without associated lymphadenopathy (Figure).

A punch biopsy revealed underlying necrotic fat. Computed tomography of the neck showed 20-mm skin thickening overlying the right zygomatic arch, with minimal adjacent subcutaneous soft tissue stranding and reactive lymph nodes. Further histologic examination of the biopsy specimen revealed inflamed granulation tissue with granulomatous inflammation.

Acid-fast bacterial culture was positive. Subsequent speciation revealed the causal agent to be multidrug-resistant Mycobacterium abscessus. The patient was initially treated with trimethoprim-sulfamethoxazole, which was switched to a combination of doxycycline and levofloxacin a few days later after initial culture returned. The following week, after the specific microorganism was confirmed with specific sensitivity, treatment was changed to intravenous (IV) tigecycline and amikacin. This regimen was continued for 2 more months through a peripherally inserted central catheter, then discontinued after complete resolution of the skin lesion.

Comment

Mycobacterial Infection
Nontuberculous mycobacteria were not identified as human pathogens until the 1950s. They are known to cause skin disease, lymphadenitis, skeletal infection, pulmonary disease, and disseminated infection, with pulmonary disease being the most common clinical form overall.¹Mycobacterium abscessus is a member of a more specific group known as rapidly growing nontuberculous mycobacteria, which also includes Mycobacterium fortuitum and Mycobacterium chelonae.² Commonly found in water, soil, and dust, M abscessus causes skin and soft tissue infection after skin injury by inoculation, minor trauma, or surgery.^2-4 An increased rate of infections recently has been attributed to an increase in cosmetic procedures such as tattooing, liposuction, mesotherapy, pedicures, and body piercing. Mycobacterial infections transmitted through acupuncture also have been documented.^5,6

Causes of Skin and Soft Tissue Infections
Skin and soft tissue infections due to rapidly growing mycobacteria often are associated with systemic comorbidities that cause immunosuppression and with immunosuppressive medications.⁷ Our patient did not have a preexisting comorbidity and did not take any long-term medication. When multiple lesions have been reported, patients were more likely to either have a systemic comorbidity or be taking immunosuppressive medication compared to patients with a single lesion. A history of penetrating trauma or an invasive surgical procedure has been reported more often in patients with a single lesion.⁷

Our patient had a solitary lesion on the face; improper sterile technique while using an at-home microdermabrasion device was thought to be the cause of infection. Although generally considered a minimally abrasive treatment modality, microdermabrasion caused enough trauma to create a nidus of infection in our patient.

Presentation
Cutaneous infection from rapidly growing mycobacteria can manifest as a nonhealing ulceration, subcutaneous abscess, draining sinus, or subcutaneous fluctuant or firm nodules. Erythema may be found in association with ulcers or chronic drainage from a surgical wound.^2,7

Histopathologic appearance varies, depending on the evolution of the disease and host immunologic status. Tuberculoid, palisading, and sarcoidlike granulomas; a diffuse infiltrate of histiocytic foamy cells; acute and chronic panniculitis; nonspecific chronic inflammation; cutaneous abscess; suppurative granuloma; and necrotizing folliculitis all can be seen.⁸ Immunosuppressed patients are less likely to form granulomas.⁶ Diagnosis often is delayed because acid-fast bacterial culture is not typically performed on skin biopsy specimens or surgical wound infections.⁷ Fortunately, a high index of suspicion in our patient’s case allowed for prompt diagnosis and expeditious management.

Management
Mycobacterium abscessus tends to be resistant to conventional antituberculous medications; overall, it is considered a highly drug-resistant pathogen that is difficult to treat.^9,10 Treatment usually requires 3 to 6 months of therapy, with oral clarithromycin considered the first-line agent for localized infection.⁵ Because cases of clarithromycin resistance have been reported in patients with M chelonae infection, caution is warranted when deciding between monotherapy or combination therapy.⁷ Multidrug resistance often necessitates prolonged IV therapy. Amikacin is the mostly commonly used IV agent for M abscessus infection. Adverse effects of treatment are common, often leading to a change in or discontinuation of therapy.¹¹

Our patient was initially given trimethoprim-sulfamethoxazole before being switched to doxycycline and levofloxacin prior to final results of susceptibility testing. Ultimately, due to the multidrug-resistant nature of M abscessus, clarithromycin was not a viable option. Therefore, the patient was administered tigecycline and amikacin through a peripherally inserted central catheter until symptoms fully resolved.

Surgery can be an important adjunctive measure for certain patients, especially those with a single lesion.⁷ Our patient did well with medical treatment alone.

Conclusion

Given the difficulty of treating skin and soft tissue infections caused by M abscessus and related mycobacteria, it is worth noting that these infections are increasingly caused by procedures generally considered to be minimally invasive. Microdermabrasion—performed at home in an unsterile environment and not by a trained medical professional—was the causal procedure in this case. An important consideration is whether clinicians can be comfortable with the use of these treatments at home or whether they should be advising patients against at-home treatments that have potentially serious complications.

Rosacea is an inflammatory skin condition that affects approximately 5% of the adult population, with the highest prevalence in Europe and North America.¹ Despite its prevalence, rosacea remains poorly understood from a pathophysiologic perspective, with no diagnostic laboratory markers.² Because diagnosis relies on clinical judgment, the nomenclature for describing and characterizing rosacea becomes paramount in ensuring that patients are given an accurate diagnosis and subsequent treatment. We review the shortfalls in the recent history of rosacea classification and discuss their implications.

Subtype to Phenotype Classification

In 2002, the National Rosacea Society (NRS) Expert Committee published a standardized classification schema for rosacea (Table).³ The authors described primary and secondary diagnostic criteria. The presence of 1 or more primary features in a central facial distribution was indicative of rosacea. Primary characteristics included flushing (transient erythema), nontransient erythema, papules and pustules, and telangiectasia. Secondary features, which could occur with or independently of primary features, included burning or stinging of the face, dry appearance, facial edema, ocular manifestations, peripheral (nonfacial) occurrence, phymatous changes, and red facial plaques. Whereas these features often present simultaneously in a characteristic pattern, they were grouped into 4 main subtypes—erythematotelangiectatic (ETR), papulopustular, phymatous, and ocular—and 1 variant, granulomatous rosacea.³

To enhance clinical and research applications of this categorization system as well as offer further standardization, the NRS released a supplementary clinical grading scorecard in 2004 in which each of the primary and secondary characteristics could be assigned a subjective severity score of absent, mild, moderate, or severe. The goal was that the subtype classification and clinical grading system, when used in conjunction with each other, would establish a common language for patients, clinicians, and researchers to describe and further investigate rosacea.⁴

The 2002 categorization system was certainly an impactful first step in the organization of rosacea. It was not without its critics, however, namely rosacea-oriented dermatologists who were concerned about its lack of specificity.^5-7 For instance, the NRS Expert Committee did not address the time frame for flushing, which typically has a long duration in rosacea patients, or for the nontransient erythema; telangiectasia secondary to heliodermatitis; or the often-observed periocular sparing. Additionally, the schema did not account for conditions such as gram-negative folliculitis (pustules characteristically located on the central face) or discuss the need to rule out carcinoid, mastocytosis, or connective-tissue disease, which can lead to nontransient facial erythema. Without strict definitions and exclusions, nonrosacea disorders could be incorrectly labeled as rosacea.

Beyond the lack of specificity, there was additional concern if a subtype system was the ideal way to capture disease presentation and severity. By subtyping, there was unnecessary division of interrelated disease into individual disorders; an individual’s clinical presentation might fall along a spectrum rather than within a discrete box.⁸

Furthermore, from a research standpoint, subtyping rosacea could hinder or confuse epidemiologic studies. For instance, if patients present with phenotypes from different subtypes, into which subtype would they fall?^8-10

The global ROSacea COnsensus (ROSCO) panel, comprising 17 international dermatologists and ophthalmologists, convened in 2016 to address this matter. The panel proposed a new system (published in 2017) based on individual phenotypes.⁹ In this new system, diagnostic features include persistent centrofacial erythema with periods of increased intensity and phymatous changes. Major features, which are diagnostic when there are at least 2, include flushing (transient erythema), inflammatory papules and pustules, centrofacial telangiectasia, and ocular manifestations. Each feature could then be graded on a severity spectrum independent of concurrent phenotypes (Table).⁸

The panel concluded that this system would provide a stronger foundation for standardization as new knowledge of rosacea continues to be elucidated.⁸ In support of their argument, ROSCO also released a treatment algorithm that depended on a phenotype scheme.¹¹ The panel emphasized that by focusing on individual lesions rather than a subtype encompassing many characteristics, treatment could be tailored to the patient. Using this à-la-carte therapy option, physicians could choose those rosacea aspects that are particularly concerning to the patient and manage only those aspects or overlap treatments to improve multiple aspects.¹¹

In 2017, 15 years after the original classification system was proposed, the NRS updated their classification system (published in 2018), taking into consideration some of the criticisms as well as new scientific data on rosacea. Similar to the schema proposed by ROSCO, this system was based on phenotype. Inclusion and exclusion criteria were more robust in this update compared to the original classification in 2002. The criteria provide a timeline for transient flushing—it must occur within seconds or minutes in response to a neurovascular stimulant—and state that it is characteristically prolonged (Table).¹²

However, the Expert Committee still did not define either the length of time of flushing or nontransient erythema. It also did not specify convex surfaces of the face with periocular sparing as the characteristic pattern or provide additional information on how photoaging fits into the definition. The updated classification stated that centrofacial erythema must not be from cutaneous lupus or seborrheic eczema, and steroid-induced rosacea was still excluded.¹² However, there is still the need to exclude other systemic conditions, such as mastocytosis, carcinoid, polycythemia vera, and dermatomyositis. Therefore, the potential for subjective error and inclusion of nonrosacea diseases persists.

A critical change was elimination of the granulomatous rosacea variant. In 2002, this variant was defined by monomorphic, yellow-brown to red papules and nodules that led to scarring. This variant, however, did not share the commonalities of the other subtypes, including persistent facial erythema, limitation to convex surfaces, periocular sparing, and transient flushing.^3,13 At the time, Crawford et al⁶ proposed that the variant be recategorized as granulomatous facial dermatitis. In the updated NRS classification, this variant and phenotypic description was eliminated from the schema.¹² It is unclear if it was removed because of these discrepancies or if the NRS panel felt it had a distinct pathogenesis from the proposed rosacea pathophysiology; however, we applaud this change.

Subtype Progression

Both the ROSCO and NRS classification schemes mention progression between the various phenotypes,^10,12 suggesting that rosacea phenotypes exist along a continuum, progressing and regressing with disease severity. The main study addressing this point was based on the self-reported retrospective patient memory of disease features in rosacea patients. The authors used a modified criterion of centrofacial erythema alone to define ETR; therefore, a person who began their disease with this finding but then acquired inflammatory lesions or phymas was defined as progressing along a spectrum.¹⁴ Given that persistent erythema of convex surfaces of the face is common in all subtypes, we do not find it surprising that the authors found (using their modified criteria) that ETR appeared to progress to papulopustular and phymatous subtypes in a small number of patients. We strongly disagree with their interpretation and conclusion.

In our experience, ETR patients have fine textured skin without sebaceous quality or a history of extensive acne (Figure 1). Flushing is common and usually lasts 10 minutes to 1 hour. There might be concurrent burning or stinging; however, there is no associated sweating, lightheadedness, palpitations, or diagnostic laboratory findings, which distinguishes ETR from other common causes of flushing. The persistent centrofacial erythema involves convex surfaces, spares periocular skin, and can be best defined as present for longer than 3 months.

Implications and Future Directions

We present an overview of 2 rosacea classification systems, hoping to stimulate further refinement. Looking forward, there are many directions for further investigation into the pathophysiology of rosacea. From a genetic standpoint, there needs to be continued molecular and epidemiologic data to determine the underlying genetic contributions to disease.

There has been some progress in the realm of understanding the mechanisms of inflammation; we urge further investigation to elucidate how “subclinical neuroinflammation” might lead to glandular hyperplasia.¹² We also see value in examining the genetic and hormonal contributions to phymas, as they may be different than those seen in the ETR-type patients. Last, more studies focusing on comorbidities that contribute to or arise from rosacea are welcomed.

The ultimate goal is to develop a classification system that integrates clinical descriptions, pathophysiologic mechanisms, and benchmark indicators of disease. Only then can we have a true gold standard for the diagnosis of rosacea, one that allows for improved personalized treatment and better outcomes.

Rosacea is an inflammatory skin condition that affects approximately 5% of the adult population, with the highest prevalence in Europe and North America.¹ Despite its prevalence, rosacea remains poorly understood from a pathophysiologic perspective, with no diagnostic laboratory markers.² Because diagnosis relies on clinical judgment, the nomenclature for describing and characterizing rosacea becomes paramount in ensuring that patients are given an accurate diagnosis and subsequent treatment. We review the shortfalls in the recent history of rosacea classification and discuss their implications.

Subtype to Phenotype Classification

In 2002, the National Rosacea Society (NRS) Expert Committee published a standardized classification schema for rosacea (Table).³ The authors described primary and secondary diagnostic criteria. The presence of 1 or more primary features in a central facial distribution was indicative of rosacea. Primary characteristics included flushing (transient erythema), nontransient erythema, papules and pustules, and telangiectasia. Secondary features, which could occur with or independently of primary features, included burning or stinging of the face, dry appearance, facial edema, ocular manifestations, peripheral (nonfacial) occurrence, phymatous changes, and red facial plaques. Whereas these features often present simultaneously in a characteristic pattern, they were grouped into 4 main subtypes—erythematotelangiectatic (ETR), papulopustular, phymatous, and ocular—and 1 variant, granulomatous rosacea.³

To enhance clinical and research applications of this categorization system as well as offer further standardization, the NRS released a supplementary clinical grading scorecard in 2004 in which each of the primary and secondary characteristics could be assigned a subjective severity score of absent, mild, moderate, or severe. The goal was that the subtype classification and clinical grading system, when used in conjunction with each other, would establish a common language for patients, clinicians, and researchers to describe and further investigate rosacea.⁴

The 2002 categorization system was certainly an impactful first step in the organization of rosacea. It was not without its critics, however, namely rosacea-oriented dermatologists who were concerned about its lack of specificity.^5-7 For instance, the NRS Expert Committee did not address the time frame for flushing, which typically has a long duration in rosacea patients, or for the nontransient erythema; telangiectasia secondary to heliodermatitis; or the often-observed periocular sparing. Additionally, the schema did not account for conditions such as gram-negative folliculitis (pustules characteristically located on the central face) or discuss the need to rule out carcinoid, mastocytosis, or connective-tissue disease, which can lead to nontransient facial erythema. Without strict definitions and exclusions, nonrosacea disorders could be incorrectly labeled as rosacea.

Beyond the lack of specificity, there was additional concern if a subtype system was the ideal way to capture disease presentation and severity. By subtyping, there was unnecessary division of interrelated disease into individual disorders; an individual’s clinical presentation might fall along a spectrum rather than within a discrete box.⁸

Furthermore, from a research standpoint, subtyping rosacea could hinder or confuse epidemiologic studies. For instance, if patients present with phenotypes from different subtypes, into which subtype would they fall?^8-10

The global ROSacea COnsensus (ROSCO) panel, comprising 17 international dermatologists and ophthalmologists, convened in 2016 to address this matter. The panel proposed a new system (published in 2017) based on individual phenotypes.⁹ In this new system, diagnostic features include persistent centrofacial erythema with periods of increased intensity and phymatous changes. Major features, which are diagnostic when there are at least 2, include flushing (transient erythema), inflammatory papules and pustules, centrofacial telangiectasia, and ocular manifestations. Each feature could then be graded on a severity spectrum independent of concurrent phenotypes (Table).⁸

The panel concluded that this system would provide a stronger foundation for standardization as new knowledge of rosacea continues to be elucidated.⁸ In support of their argument, ROSCO also released a treatment algorithm that depended on a phenotype scheme.¹¹ The panel emphasized that by focusing on individual lesions rather than a subtype encompassing many characteristics, treatment could be tailored to the patient. Using this à-la-carte therapy option, physicians could choose those rosacea aspects that are particularly concerning to the patient and manage only those aspects or overlap treatments to improve multiple aspects.¹¹

In 2017, 15 years after the original classification system was proposed, the NRS updated their classification system (published in 2018), taking into consideration some of the criticisms as well as new scientific data on rosacea. Similar to the schema proposed by ROSCO, this system was based on phenotype. Inclusion and exclusion criteria were more robust in this update compared to the original classification in 2002. The criteria provide a timeline for transient flushing—it must occur within seconds or minutes in response to a neurovascular stimulant—and state that it is characteristically prolonged (Table).¹²

However, the Expert Committee still did not define either the length of time of flushing or nontransient erythema. It also did not specify convex surfaces of the face with periocular sparing as the characteristic pattern or provide additional information on how photoaging fits into the definition. The updated classification stated that centrofacial erythema must not be from cutaneous lupus or seborrheic eczema, and steroid-induced rosacea was still excluded.¹² However, there is still the need to exclude other systemic conditions, such as mastocytosis, carcinoid, polycythemia vera, and dermatomyositis. Therefore, the potential for subjective error and inclusion of nonrosacea diseases persists.

A critical change was elimination of the granulomatous rosacea variant. In 2002, this variant was defined by monomorphic, yellow-brown to red papules and nodules that led to scarring. This variant, however, did not share the commonalities of the other subtypes, including persistent facial erythema, limitation to convex surfaces, periocular sparing, and transient flushing.^3,13 At the time, Crawford et al⁶ proposed that the variant be recategorized as granulomatous facial dermatitis. In the updated NRS classification, this variant and phenotypic description was eliminated from the schema.¹² It is unclear if it was removed because of these discrepancies or if the NRS panel felt it had a distinct pathogenesis from the proposed rosacea pathophysiology; however, we applaud this change.

Subtype Progression

Both the ROSCO and NRS classification schemes mention progression between the various phenotypes,^10,12 suggesting that rosacea phenotypes exist along a continuum, progressing and regressing with disease severity. The main study addressing this point was based on the self-reported retrospective patient memory of disease features in rosacea patients. The authors used a modified criterion of centrofacial erythema alone to define ETR; therefore, a person who began their disease with this finding but then acquired inflammatory lesions or phymas was defined as progressing along a spectrum.¹⁴ Given that persistent erythema of convex surfaces of the face is common in all subtypes, we do not find it surprising that the authors found (using their modified criteria) that ETR appeared to progress to papulopustular and phymatous subtypes in a small number of patients. We strongly disagree with their interpretation and conclusion.

In our experience, ETR patients have fine textured skin without sebaceous quality or a history of extensive acne (Figure 1). Flushing is common and usually lasts 10 minutes to 1 hour. There might be concurrent burning or stinging; however, there is no associated sweating, lightheadedness, palpitations, or diagnostic laboratory findings, which distinguishes ETR from other common causes of flushing. The persistent centrofacial erythema involves convex surfaces, spares periocular skin, and can be best defined as present for longer than 3 months.

Implications and Future Directions

We present an overview of 2 rosacea classification systems, hoping to stimulate further refinement. Looking forward, there are many directions for further investigation into the pathophysiology of rosacea. From a genetic standpoint, there needs to be continued molecular and epidemiologic data to determine the underlying genetic contributions to disease.

There has been some progress in the realm of understanding the mechanisms of inflammation; we urge further investigation to elucidate how “subclinical neuroinflammation” might lead to glandular hyperplasia.¹² We also see value in examining the genetic and hormonal contributions to phymas, as they may be different than those seen in the ETR-type patients. Last, more studies focusing on comorbidities that contribute to or arise from rosacea are welcomed.

The ultimate goal is to develop a classification system that integrates clinical descriptions, pathophysiologic mechanisms, and benchmark indicators of disease. Only then can we have a true gold standard for the diagnosis of rosacea, one that allows for improved personalized treatment and better outcomes.

Rosacea is an inflammatory skin condition that affects approximately 5% of the adult population, with the highest prevalence in Europe and North America.¹ Despite its prevalence, rosacea remains poorly understood from a pathophysiologic perspective, with no diagnostic laboratory markers.² Because diagnosis relies on clinical judgment, the nomenclature for describing and characterizing rosacea becomes paramount in ensuring that patients are given an accurate diagnosis and subsequent treatment. We review the shortfalls in the recent history of rosacea classification and discuss their implications.

Subtype to Phenotype Classification

In 2002, the National Rosacea Society (NRS) Expert Committee published a standardized classification schema for rosacea (Table).³ The authors described primary and secondary diagnostic criteria. The presence of 1 or more primary features in a central facial distribution was indicative of rosacea. Primary characteristics included flushing (transient erythema), nontransient erythema, papules and pustules, and telangiectasia. Secondary features, which could occur with or independently of primary features, included burning or stinging of the face, dry appearance, facial edema, ocular manifestations, peripheral (nonfacial) occurrence, phymatous changes, and red facial plaques. Whereas these features often present simultaneously in a characteristic pattern, they were grouped into 4 main subtypes—erythematotelangiectatic (ETR), papulopustular, phymatous, and ocular—and 1 variant, granulomatous rosacea.³

To enhance clinical and research applications of this categorization system as well as offer further standardization, the NRS released a supplementary clinical grading scorecard in 2004 in which each of the primary and secondary characteristics could be assigned a subjective severity score of absent, mild, moderate, or severe. The goal was that the subtype classification and clinical grading system, when used in conjunction with each other, would establish a common language for patients, clinicians, and researchers to describe and further investigate rosacea.⁴

The 2002 categorization system was certainly an impactful first step in the organization of rosacea. It was not without its critics, however, namely rosacea-oriented dermatologists who were concerned about its lack of specificity.^5-7 For instance, the NRS Expert Committee did not address the time frame for flushing, which typically has a long duration in rosacea patients, or for the nontransient erythema; telangiectasia secondary to heliodermatitis; or the often-observed periocular sparing. Additionally, the schema did not account for conditions such as gram-negative folliculitis (pustules characteristically located on the central face) or discuss the need to rule out carcinoid, mastocytosis, or connective-tissue disease, which can lead to nontransient facial erythema. Without strict definitions and exclusions, nonrosacea disorders could be incorrectly labeled as rosacea.

Beyond the lack of specificity, there was additional concern if a subtype system was the ideal way to capture disease presentation and severity. By subtyping, there was unnecessary division of interrelated disease into individual disorders; an individual’s clinical presentation might fall along a spectrum rather than within a discrete box.⁸

Furthermore, from a research standpoint, subtyping rosacea could hinder or confuse epidemiologic studies. For instance, if patients present with phenotypes from different subtypes, into which subtype would they fall?^8-10

The global ROSacea COnsensus (ROSCO) panel, comprising 17 international dermatologists and ophthalmologists, convened in 2016 to address this matter. The panel proposed a new system (published in 2017) based on individual phenotypes.⁹ In this new system, diagnostic features include persistent centrofacial erythema with periods of increased intensity and phymatous changes. Major features, which are diagnostic when there are at least 2, include flushing (transient erythema), inflammatory papules and pustules, centrofacial telangiectasia, and ocular manifestations. Each feature could then be graded on a severity spectrum independent of concurrent phenotypes (Table).⁸

The panel concluded that this system would provide a stronger foundation for standardization as new knowledge of rosacea continues to be elucidated.⁸ In support of their argument, ROSCO also released a treatment algorithm that depended on a phenotype scheme.¹¹ The panel emphasized that by focusing on individual lesions rather than a subtype encompassing many characteristics, treatment could be tailored to the patient. Using this à-la-carte therapy option, physicians could choose those rosacea aspects that are particularly concerning to the patient and manage only those aspects or overlap treatments to improve multiple aspects.¹¹

In 2017, 15 years after the original classification system was proposed, the NRS updated their classification system (published in 2018), taking into consideration some of the criticisms as well as new scientific data on rosacea. Similar to the schema proposed by ROSCO, this system was based on phenotype. Inclusion and exclusion criteria were more robust in this update compared to the original classification in 2002. The criteria provide a timeline for transient flushing—it must occur within seconds or minutes in response to a neurovascular stimulant—and state that it is characteristically prolonged (Table).¹²

However, the Expert Committee still did not define either the length of time of flushing or nontransient erythema. It also did not specify convex surfaces of the face with periocular sparing as the characteristic pattern or provide additional information on how photoaging fits into the definition. The updated classification stated that centrofacial erythema must not be from cutaneous lupus or seborrheic eczema, and steroid-induced rosacea was still excluded.¹² However, there is still the need to exclude other systemic conditions, such as mastocytosis, carcinoid, polycythemia vera, and dermatomyositis. Therefore, the potential for subjective error and inclusion of nonrosacea diseases persists.

A critical change was elimination of the granulomatous rosacea variant. In 2002, this variant was defined by monomorphic, yellow-brown to red papules and nodules that led to scarring. This variant, however, did not share the commonalities of the other subtypes, including persistent facial erythema, limitation to convex surfaces, periocular sparing, and transient flushing.^3,13 At the time, Crawford et al⁶ proposed that the variant be recategorized as granulomatous facial dermatitis. In the updated NRS classification, this variant and phenotypic description was eliminated from the schema.¹² It is unclear if it was removed because of these discrepancies or if the NRS panel felt it had a distinct pathogenesis from the proposed rosacea pathophysiology; however, we applaud this change.

Subtype Progression

Both the ROSCO and NRS classification schemes mention progression between the various phenotypes,^10,12 suggesting that rosacea phenotypes exist along a continuum, progressing and regressing with disease severity. The main study addressing this point was based on the self-reported retrospective patient memory of disease features in rosacea patients. The authors used a modified criterion of centrofacial erythema alone to define ETR; therefore, a person who began their disease with this finding but then acquired inflammatory lesions or phymas was defined as progressing along a spectrum.¹⁴ Given that persistent erythema of convex surfaces of the face is common in all subtypes, we do not find it surprising that the authors found (using their modified criteria) that ETR appeared to progress to papulopustular and phymatous subtypes in a small number of patients. We strongly disagree with their interpretation and conclusion.

In our experience, ETR patients have fine textured skin without sebaceous quality or a history of extensive acne (Figure 1). Flushing is common and usually lasts 10 minutes to 1 hour. There might be concurrent burning or stinging; however, there is no associated sweating, lightheadedness, palpitations, or diagnostic laboratory findings, which distinguishes ETR from other common causes of flushing. The persistent centrofacial erythema involves convex surfaces, spares periocular skin, and can be best defined as present for longer than 3 months.

Implications and Future Directions

We present an overview of 2 rosacea classification systems, hoping to stimulate further refinement. Looking forward, there are many directions for further investigation into the pathophysiology of rosacea. From a genetic standpoint, there needs to be continued molecular and epidemiologic data to determine the underlying genetic contributions to disease.

There has been some progress in the realm of understanding the mechanisms of inflammation; we urge further investigation to elucidate how “subclinical neuroinflammation” might lead to glandular hyperplasia.¹² We also see value in examining the genetic and hormonal contributions to phymas, as they may be different than those seen in the ETR-type patients. Last, more studies focusing on comorbidities that contribute to or arise from rosacea are welcomed.

The ultimate goal is to develop a classification system that integrates clinical descriptions, pathophysiologic mechanisms, and benchmark indicators of disease. Only then can we have a true gold standard for the diagnosis of rosacea, one that allows for improved personalized treatment and better outcomes.

In the last 20 years, the incidence of acne lesions in adults has markedly increased. ¹ Acne affects adults (individuals older than 25 years) and is no longer a condition limited to adolescents and young adults (individuals younger than 25 years). According to Dreno et al, ² the accepted age threshold for the onset of adult acne is 25 years. ^1-3 In 2013, the term adult acne was defined. ² Among patients with adult acne, there are 2 subtypes: (1) persistent adult acne, which is a continuation or recurrence of adolescent acne, affecting approximately 80% of patients, and (2) late-onset acne, affecting approximately 20% of patients. ⁴

Clinical symptoms of adult acne and available treatment modalities have been explored in the literature. Daily clinical experience shows that additional difficulties involved in the management of adult acne patients are related mainly to a high therapeutic failure rate in acne patients older than 25 years. ⁵ Persistent adult acne seems to be noteworthy because it causes long-term symptoms, and patients experience uncontrollable recurrences.

It is believed that adult acne often is resistant to treatment. ² Adult skin is more sensitive to topical agents, leading to more irritation by medications intended for external use and cosmetics. ⁶ Scars in these patients are a frequent and undesirable consequence. ³

Effective treatment of acne encompasses oral antibiotics, topical and systemic retinoids, and oral contraceptive pills (OCPs). For years, oral subantimicrobial doses of cyclines have been recommended for acne treatment. Topical and oral retinoids have been successfully used for more than 30 years as important therapeutic options. ⁷ More recent evidence-based guidelines for acne issued by the American Academy of Dermatology ⁸ and the European Dermatology Forum ⁹ also show that retinoids play an important role in acne therapy. Their anti-inflammatory activity acts against comedones and their precursors (microcomedones). Successful antiacne therapy not only achieves a smooth face without comedones but also minimizes scar formation, postinflammatory discoloration, and long-lasting postinflammatory erythema. ¹⁰ Oral contraceptives have a mainly antiseborrheic effect. ¹¹

Our study sought to analyze the potential influence of therapy during adolescent acne on patients who later developed adult acne. Particular attention was given to the use of oral antibiotics, isotretinoin, and topical retinoids for adolescent acne and their potential role in diminishing scar formation in adult acne.

Materials and Methods

Patient Demographics and Selection
A population-based study of Polish patients with adult acne was conducted. Patients were included in the study group on a consecutive basis from among those who visited our outpatient dermatology center from May 2015 to January 2016. A total of 111 patients (101 women [90.99%] and 10 men [9.01%]) were examined. The study group comprised patients aged 25 years and older who were treated for adult acne (20 patients [18.02%] were aged 25–29 years, 61 [54.95%] were aged 30–39 years, and 30 [27.02%] were 40 years or older).

The following inclusion criteria were used: observation period of at least 6 months in our dermatologic center for patients diagnosed with adult acne, at least 2 dermatologic visits for adult acne prior to the study, written informed consent for study participation and data processing (the aim of the study was explained to each participant by a dermatologist), and age 25 years or older. Exclusion criteria included those who were younger than 25 years, those who had only 1 dermatologic visit at our dermatology center, and those who were unwilling to participate or did not provide written informed consent. Our study was conducted according to Good Clinical Practice.

Data Collection
To obtain data with the highest degree of reliability, 3 sources of information were used: (1) a detailed medical interview conducted by one experienced dermatologist (E.C.) at our dermatology center at the first visit in all study participants, (2) a clinical examination that yielded results necessary for the assessment of scars using a method outlined by Jacob et al, ¹² and (3) information included in available medical records. These data were then statistically analyzed.

Statistical Analysis
The results were presented as frequency plots, and a Fisher exact test was conducted to obtain a statistical comparison of the distributions of analyzed data. Unless otherwise indicated, 5% was adopted as the significance level. The statistical analysis was performed using Stata 14 software (StataCorp LLC, College Station, Texas).

Results

Incidence of Different Forms of Adult Acne
To analyze the onset of acne, patients were categorized into 1 of 2 groups: those with persistent adult acne (81.98%) and those with late-onset adult acne (ie, developed after 25 years of age)(18.02%).

Age at Initiation of Dermatologic Treatment
Of the patients with persistent adult acne, 31.87% first visited a dermatologist the same year that the first acne lesions appeared, 36.26% postponed the first visit by at least 5 years (Figure 1), and 23.08% started treatment at least 10 years after acne first appeared. Among patients with persistent adult acne, 76.92% began dermatologic treatment before 25 years of age, and 23.08% began treatment after 25 years of age. Of the latter, 28.57% did not start therapy until they were older than 35 years.

Severity of Adolescent Acne
In the persistent adult acne group, the severity of adolescent acne was assessed during the medical interview as well as detailed histories in medical records. The activity of acne was evaluated at 2-year intervals with the use of a 10-point scale: 1 to 3 points indicated mild acne (7.69% of patients), 4 to 6 points indicated moderate acne (24.18%), and 7 to 10 points indicated severe acne (68.13%).

Treatment of Persistent Acne in Adolescence
Treatment was comprised of oral therapy with antibiotics, isotretinoin, and/or application of topical retinoids (sometimes supported with OCPs). Monotherapy was the standard of treatment more than 25 years ago when patients with persistent adult acne were treated as adolescents or young adults. As many as 43.96% of patients with persistent adult acne did not receive any of these therapies before 25 years of age; rather, they used antiacne cosmetics or beauty procedures. Furthermore, 50.55% of patients were treated with oral antibiotics (Figure 2). Topical retinoids were used in 19.78% of patients and isotretinoin was used in 16.48%. Incidentally, OCPs were given to 26.5%. In the course of adolescent acne, 31.87% of patients received 2 to 4 courses of treatment with either antibiotics or retinoids (oral or topical), and 5.49% were treated with 5 or more courses of treatment (Figure 3). The analysis of each treatment revealed that only 1 patient received 4 courses of isotretinoin. Five courses of oral antibiotics were given in 1 patient, and 3 courses of topical retinoids were given in the same patient.

Topical Retinoids
In an analysis of the number of treatments with topical retinoids completed by patients with persistent adult acne, it was established that 80.22% of patients never used topical retinoids for acne during adolescence. Additionally, 12.08% of these patients completed 1 course of treatment, and 7.69% completed 2 to 4 treatments. However, after 25 years of age, only 25.27% of the patients with persistent adult acne were not treated with topical retinoids, and 35.16% completed more than 2 courses of treatment.

Duration of Treatment
Because adult acne is a chronic disease, the mean number of years that patients received treatment over the disease course was analyzed. In the case of persistent adult acne, the mean duration of treatment, including therapy received during adolescence, was more than 13 years. At the time of the study, more than 30% of patients had been undergoing treatment of adult acne for more than 20 years. Scars— The proportion of patients with persistent adult acne who experienced scarring was evaluated. In the persistent adult acne group, scars were identified in 53.85% of patients. Scars appeared only during adolescence in 26.37% of patients with persistent adult acne, scars appeared only after 25 years of age in 21.97% of patients, and scars appeared in adolescence as well as adulthood in 30.77% of patients.

In an analysis of patients with persistent adult acne who experienced scarring after 25 years of age, the proportion of patients with untreated adolescent acne and those who were treated with antibiotics only was not significantly different (60% vs 64%; P = .478)(Table). The inclusion of topical retinoids into treatment decreased the proportion of scars (isotretinoin: 20%, P = .009; topical retinoids: 38.89%, P = .114).

Comment

Persistent Adult Acne
Patients with symptoms of persistent adult acne represented 81.98% of the study population, which was similar to a 1999 study by Goulden et al, ¹ a 2001 study by Shaw and White, ¹³ and a 2009 report by Schmidt et al. ¹⁴ Of these patients with persistent adult acne, 23.08% initiated therapy after 25 years of age, and 23.08% started treatment at least 10 years after acne lesions first appeared. However, it is noteworthy that 68.13% of all patients with persistent adult acne assessed their disease as severe.

Treatment Modalities for Adult Acne
Over the last 5 years, some researchers have attempted to make recommendations for the treatment of adult acne based on standards adopted for the treatment of adolescent acne. ^2,9,15 First-line treatment of patients with adult comedonal acne is topical retinoids. ⁹ The recommended treatment of mild to moderate adult inflammatory acne involves topical drugs, including retinoids, azelaic acid, or benzoyl peroxide, or oral medications, including antibiotics, OCPs, or antiandrogens. In severe inflammatory acne, the recommended treatment involves oral isotretinoin or combined therapies; the latter seems to be the most effective. ¹⁶ Furthermore, this therapy has been adjusted to the patient’s current clinical condition; general individual sensitivity of the skin to irritation and the risk for irritant activity of topical medications; and life situation, such as planned pregnancies and intended use of OCPs due to the risk for teratogenic effects of drugs. ¹⁷

To assess available treatment modalities, oral therapy with antibiotics or isotretinoin as well as topical retinoids were selected for our analysis. It is difficult to determine an exclusive impact of OCPs as acne treatment; according to our study, many female patients use hormone therapy for other medical conditions or contraception, and only a small proportion of these patients are prescribed hormone treatment for acne. We found that 43.96% of patients with persistent adult acne underwent no treatment with antibiotics, isotretinoin, or topical retinoids in adolescence. Patients who did not receive any of these treatments came only for single visits to a dermatologist, did not comply to a recommended therapy, or used only cosmetics or beauty procedures. We found that 80.22% of patients with persistent adult acne never used topical retinoids during adolescence and did not receive maintenance therapy, which may be attributed to the fact that there were no strict recommendations regarding retinoid treatment when these patients were adolescents or young adults. Published data indicate that retinoid use for acne treatment is not common. ¹⁸ Conversely, among patients older than 25 years with late-onset adult acne, there was only 1 patient (ie, < 1%) who had never received any oral antibiotic or isotretinoin treatment or therapy with topical retinoids. The reason for the lack of medical treatment is unknown. Only 25.27% of patients were not treated with topical retinoids, and 35.16% completed at least 2 courses of treatment. The use of topical retinoids for the treatment of persistent and late-onset adult acne may be the result of the spread of knowledge among dermatologists acquired over the last 25 years.

Acne Scarring
The worst complication of acne is scarring. Scars develop for the duration of the disease, during both adolescent and adult acne. In the group with persistent adult acne, scarring was found in 53.85% of patients. Scar formation has been previously reported as a common complication of acne. ¹⁹ The effects of skin lesions that remain after acne are not only limited to impaired cosmetic appearance; they also negatively affect mental health and impair quality of life. ²⁰ The aim of our study was to analyze types of treatment for adolescent acne in patients who later had persistent adult acne. Postacne scars observed later are objective evidence of the severity of disease. We found that using oral antibiotics did not diminish the number of scars among persistent adult acne patients in adulthood. In contrast, isotretinoin or topical retinoid treatment during adolescence decreased the risk for scars occurring during adulthood. In our opinion, these findings emphasize the role of this type of treatment among adolescents or young adults. The decrease of scar formation in adult acne due to retinoid treatment in adolescence indirectly justifies the role of maintenance therapy with topical retinoids. ^21,22

In the last 20 years, the incidence of acne lesions in adults has markedly increased. ¹ Acne affects adults (individuals older than 25 years) and is no longer a condition limited to adolescents and young adults (individuals younger than 25 years). According to Dreno et al, ² the accepted age threshold for the onset of adult acne is 25 years. ^1-3 In 2013, the term adult acne was defined. ² Among patients with adult acne, there are 2 subtypes: (1) persistent adult acne, which is a continuation or recurrence of adolescent acne, affecting approximately 80% of patients, and (2) late-onset acne, affecting approximately 20% of patients. ⁴

Clinical symptoms of adult acne and available treatment modalities have been explored in the literature. Daily clinical experience shows that additional difficulties involved in the management of adult acne patients are related mainly to a high therapeutic failure rate in acne patients older than 25 years. ⁵ Persistent adult acne seems to be noteworthy because it causes long-term symptoms, and patients experience uncontrollable recurrences.

It is believed that adult acne often is resistant to treatment. ² Adult skin is more sensitive to topical agents, leading to more irritation by medications intended for external use and cosmetics. ⁶ Scars in these patients are a frequent and undesirable consequence. ³

Effective treatment of acne encompasses oral antibiotics, topical and systemic retinoids, and oral contraceptive pills (OCPs). For years, oral subantimicrobial doses of cyclines have been recommended for acne treatment. Topical and oral retinoids have been successfully used for more than 30 years as important therapeutic options. ⁷ More recent evidence-based guidelines for acne issued by the American Academy of Dermatology ⁸ and the European Dermatology Forum ⁹ also show that retinoids play an important role in acne therapy. Their anti-inflammatory activity acts against comedones and their precursors (microcomedones). Successful antiacne therapy not only achieves a smooth face without comedones but also minimizes scar formation, postinflammatory discoloration, and long-lasting postinflammatory erythema. ¹⁰ Oral contraceptives have a mainly antiseborrheic effect. ¹¹

Our study sought to analyze the potential influence of therapy during adolescent acne on patients who later developed adult acne. Particular attention was given to the use of oral antibiotics, isotretinoin, and topical retinoids for adolescent acne and their potential role in diminishing scar formation in adult acne.

Materials and Methods

Patient Demographics and Selection
A population-based study of Polish patients with adult acne was conducted. Patients were included in the study group on a consecutive basis from among those who visited our outpatient dermatology center from May 2015 to January 2016. A total of 111 patients (101 women [90.99%] and 10 men [9.01%]) were examined. The study group comprised patients aged 25 years and older who were treated for adult acne (20 patients [18.02%] were aged 25–29 years, 61 [54.95%] were aged 30–39 years, and 30 [27.02%] were 40 years or older).

The following inclusion criteria were used: observation period of at least 6 months in our dermatologic center for patients diagnosed with adult acne, at least 2 dermatologic visits for adult acne prior to the study, written informed consent for study participation and data processing (the aim of the study was explained to each participant by a dermatologist), and age 25 years or older. Exclusion criteria included those who were younger than 25 years, those who had only 1 dermatologic visit at our dermatology center, and those who were unwilling to participate or did not provide written informed consent. Our study was conducted according to Good Clinical Practice.

Data Collection
To obtain data with the highest degree of reliability, 3 sources of information were used: (1) a detailed medical interview conducted by one experienced dermatologist (E.C.) at our dermatology center at the first visit in all study participants, (2) a clinical examination that yielded results necessary for the assessment of scars using a method outlined by Jacob et al, ¹² and (3) information included in available medical records. These data were then statistically analyzed.

Statistical Analysis
The results were presented as frequency plots, and a Fisher exact test was conducted to obtain a statistical comparison of the distributions of analyzed data. Unless otherwise indicated, 5% was adopted as the significance level. The statistical analysis was performed using Stata 14 software (StataCorp LLC, College Station, Texas).

Results

Incidence of Different Forms of Adult Acne
To analyze the onset of acne, patients were categorized into 1 of 2 groups: those with persistent adult acne (81.98%) and those with late-onset adult acne (ie, developed after 25 years of age)(18.02%).

Age at Initiation of Dermatologic Treatment
Of the patients with persistent adult acne, 31.87% first visited a dermatologist the same year that the first acne lesions appeared, 36.26% postponed the first visit by at least 5 years (Figure 1), and 23.08% started treatment at least 10 years after acne first appeared. Among patients with persistent adult acne, 76.92% began dermatologic treatment before 25 years of age, and 23.08% began treatment after 25 years of age. Of the latter, 28.57% did not start therapy until they were older than 35 years.

Severity of Adolescent Acne
In the persistent adult acne group, the severity of adolescent acne was assessed during the medical interview as well as detailed histories in medical records. The activity of acne was evaluated at 2-year intervals with the use of a 10-point scale: 1 to 3 points indicated mild acne (7.69% of patients), 4 to 6 points indicated moderate acne (24.18%), and 7 to 10 points indicated severe acne (68.13%).

Treatment of Persistent Acne in Adolescence
Treatment was comprised of oral therapy with antibiotics, isotretinoin, and/or application of topical retinoids (sometimes supported with OCPs). Monotherapy was the standard of treatment more than 25 years ago when patients with persistent adult acne were treated as adolescents or young adults. As many as 43.96% of patients with persistent adult acne did not receive any of these therapies before 25 years of age; rather, they used antiacne cosmetics or beauty procedures. Furthermore, 50.55% of patients were treated with oral antibiotics (Figure 2). Topical retinoids were used in 19.78% of patients and isotretinoin was used in 16.48%. Incidentally, OCPs were given to 26.5%. In the course of adolescent acne, 31.87% of patients received 2 to 4 courses of treatment with either antibiotics or retinoids (oral or topical), and 5.49% were treated with 5 or more courses of treatment (Figure 3). The analysis of each treatment revealed that only 1 patient received 4 courses of isotretinoin. Five courses of oral antibiotics were given in 1 patient, and 3 courses of topical retinoids were given in the same patient.

Topical Retinoids
In an analysis of the number of treatments with topical retinoids completed by patients with persistent adult acne, it was established that 80.22% of patients never used topical retinoids for acne during adolescence. Additionally, 12.08% of these patients completed 1 course of treatment, and 7.69% completed 2 to 4 treatments. However, after 25 years of age, only 25.27% of the patients with persistent adult acne were not treated with topical retinoids, and 35.16% completed more than 2 courses of treatment.

Duration of Treatment
Because adult acne is a chronic disease, the mean number of years that patients received treatment over the disease course was analyzed. In the case of persistent adult acne, the mean duration of treatment, including therapy received during adolescence, was more than 13 years. At the time of the study, more than 30% of patients had been undergoing treatment of adult acne for more than 20 years. Scars— The proportion of patients with persistent adult acne who experienced scarring was evaluated. In the persistent adult acne group, scars were identified in 53.85% of patients. Scars appeared only during adolescence in 26.37% of patients with persistent adult acne, scars appeared only after 25 years of age in 21.97% of patients, and scars appeared in adolescence as well as adulthood in 30.77% of patients.

In an analysis of patients with persistent adult acne who experienced scarring after 25 years of age, the proportion of patients with untreated adolescent acne and those who were treated with antibiotics only was not significantly different (60% vs 64%; P = .478)(Table). The inclusion of topical retinoids into treatment decreased the proportion of scars (isotretinoin: 20%, P = .009; topical retinoids: 38.89%, P = .114).

Comment

Persistent Adult Acne
Patients with symptoms of persistent adult acne represented 81.98% of the study population, which was similar to a 1999 study by Goulden et al, ¹ a 2001 study by Shaw and White, ¹³ and a 2009 report by Schmidt et al. ¹⁴ Of these patients with persistent adult acne, 23.08% initiated therapy after 25 years of age, and 23.08% started treatment at least 10 years after acne lesions first appeared. However, it is noteworthy that 68.13% of all patients with persistent adult acne assessed their disease as severe.

Treatment Modalities for Adult Acne
Over the last 5 years, some researchers have attempted to make recommendations for the treatment of adult acne based on standards adopted for the treatment of adolescent acne. ^2,9,15 First-line treatment of patients with adult comedonal acne is topical retinoids. ⁹ The recommended treatment of mild to moderate adult inflammatory acne involves topical drugs, including retinoids, azelaic acid, or benzoyl peroxide, or oral medications, including antibiotics, OCPs, or antiandrogens. In severe inflammatory acne, the recommended treatment involves oral isotretinoin or combined therapies; the latter seems to be the most effective. ¹⁶ Furthermore, this therapy has been adjusted to the patient’s current clinical condition; general individual sensitivity of the skin to irritation and the risk for irritant activity of topical medications; and life situation, such as planned pregnancies and intended use of OCPs due to the risk for teratogenic effects of drugs. ¹⁷

To assess available treatment modalities, oral therapy with antibiotics or isotretinoin as well as topical retinoids were selected for our analysis. It is difficult to determine an exclusive impact of OCPs as acne treatment; according to our study, many female patients use hormone therapy for other medical conditions or contraception, and only a small proportion of these patients are prescribed hormone treatment for acne. We found that 43.96% of patients with persistent adult acne underwent no treatment with antibiotics, isotretinoin, or topical retinoids in adolescence. Patients who did not receive any of these treatments came only for single visits to a dermatologist, did not comply to a recommended therapy, or used only cosmetics or beauty procedures. We found that 80.22% of patients with persistent adult acne never used topical retinoids during adolescence and did not receive maintenance therapy, which may be attributed to the fact that there were no strict recommendations regarding retinoid treatment when these patients were adolescents or young adults. Published data indicate that retinoid use for acne treatment is not common. ¹⁸ Conversely, among patients older than 25 years with late-onset adult acne, there was only 1 patient (ie, < 1%) who had never received any oral antibiotic or isotretinoin treatment or therapy with topical retinoids. The reason for the lack of medical treatment is unknown. Only 25.27% of patients were not treated with topical retinoids, and 35.16% completed at least 2 courses of treatment. The use of topical retinoids for the treatment of persistent and late-onset adult acne may be the result of the spread of knowledge among dermatologists acquired over the last 25 years.

Acne Scarring
The worst complication of acne is scarring. Scars develop for the duration of the disease, during both adolescent and adult acne. In the group with persistent adult acne, scarring was found in 53.85% of patients. Scar formation has been previously reported as a common complication of acne. ¹⁹ The effects of skin lesions that remain after acne are not only limited to impaired cosmetic appearance; they also negatively affect mental health and impair quality of life. ²⁰ The aim of our study was to analyze types of treatment for adolescent acne in patients who later had persistent adult acne. Postacne scars observed later are objective evidence of the severity of disease. We found that using oral antibiotics did not diminish the number of scars among persistent adult acne patients in adulthood. In contrast, isotretinoin or topical retinoid treatment during adolescence decreased the risk for scars occurring during adulthood. In our opinion, these findings emphasize the role of this type of treatment among adolescents or young adults. The decrease of scar formation in adult acne due to retinoid treatment in adolescence indirectly justifies the role of maintenance therapy with topical retinoids. ^21,22

In the last 20 years, the incidence of acne lesions in adults has markedly increased. ¹ Acne affects adults (individuals older than 25 years) and is no longer a condition limited to adolescents and young adults (individuals younger than 25 years). According to Dreno et al, ² the accepted age threshold for the onset of adult acne is 25 years. ^1-3 In 2013, the term adult acne was defined. ² Among patients with adult acne, there are 2 subtypes: (1) persistent adult acne, which is a continuation or recurrence of adolescent acne, affecting approximately 80% of patients, and (2) late-onset acne, affecting approximately 20% of patients. ⁴

Clinical symptoms of adult acne and available treatment modalities have been explored in the literature. Daily clinical experience shows that additional difficulties involved in the management of adult acne patients are related mainly to a high therapeutic failure rate in acne patients older than 25 years. ⁵ Persistent adult acne seems to be noteworthy because it causes long-term symptoms, and patients experience uncontrollable recurrences.

It is believed that adult acne often is resistant to treatment. ² Adult skin is more sensitive to topical agents, leading to more irritation by medications intended for external use and cosmetics. ⁶ Scars in these patients are a frequent and undesirable consequence. ³

Effective treatment of acne encompasses oral antibiotics, topical and systemic retinoids, and oral contraceptive pills (OCPs). For years, oral subantimicrobial doses of cyclines have been recommended for acne treatment. Topical and oral retinoids have been successfully used for more than 30 years as important therapeutic options. ⁷ More recent evidence-based guidelines for acne issued by the American Academy of Dermatology ⁸ and the European Dermatology Forum ⁹ also show that retinoids play an important role in acne therapy. Their anti-inflammatory activity acts against comedones and their precursors (microcomedones). Successful antiacne therapy not only achieves a smooth face without comedones but also minimizes scar formation, postinflammatory discoloration, and long-lasting postinflammatory erythema. ¹⁰ Oral contraceptives have a mainly antiseborrheic effect. ¹¹

Our study sought to analyze the potential influence of therapy during adolescent acne on patients who later developed adult acne. Particular attention was given to the use of oral antibiotics, isotretinoin, and topical retinoids for adolescent acne and their potential role in diminishing scar formation in adult acne.

Materials and Methods

Patient Demographics and Selection
A population-based study of Polish patients with adult acne was conducted. Patients were included in the study group on a consecutive basis from among those who visited our outpatient dermatology center from May 2015 to January 2016. A total of 111 patients (101 women [90.99%] and 10 men [9.01%]) were examined. The study group comprised patients aged 25 years and older who were treated for adult acne (20 patients [18.02%] were aged 25–29 years, 61 [54.95%] were aged 30–39 years, and 30 [27.02%] were 40 years or older).

The following inclusion criteria were used: observation period of at least 6 months in our dermatologic center for patients diagnosed with adult acne, at least 2 dermatologic visits for adult acne prior to the study, written informed consent for study participation and data processing (the aim of the study was explained to each participant by a dermatologist), and age 25 years or older. Exclusion criteria included those who were younger than 25 years, those who had only 1 dermatologic visit at our dermatology center, and those who were unwilling to participate or did not provide written informed consent. Our study was conducted according to Good Clinical Practice.

Data Collection
To obtain data with the highest degree of reliability, 3 sources of information were used: (1) a detailed medical interview conducted by one experienced dermatologist (E.C.) at our dermatology center at the first visit in all study participants, (2) a clinical examination that yielded results necessary for the assessment of scars using a method outlined by Jacob et al, ¹² and (3) information included in available medical records. These data were then statistically analyzed.

Statistical Analysis
The results were presented as frequency plots, and a Fisher exact test was conducted to obtain a statistical comparison of the distributions of analyzed data. Unless otherwise indicated, 5% was adopted as the significance level. The statistical analysis was performed using Stata 14 software (StataCorp LLC, College Station, Texas).

Results

Incidence of Different Forms of Adult Acne
To analyze the onset of acne, patients were categorized into 1 of 2 groups: those with persistent adult acne (81.98%) and those with late-onset adult acne (ie, developed after 25 years of age)(18.02%).

Age at Initiation of Dermatologic Treatment
Of the patients with persistent adult acne, 31.87% first visited a dermatologist the same year that the first acne lesions appeared, 36.26% postponed the first visit by at least 5 years (Figure 1), and 23.08% started treatment at least 10 years after acne first appeared. Among patients with persistent adult acne, 76.92% began dermatologic treatment before 25 years of age, and 23.08% began treatment after 25 years of age. Of the latter, 28.57% did not start therapy until they were older than 35 years.

Severity of Adolescent Acne
In the persistent adult acne group, the severity of adolescent acne was assessed during the medical interview as well as detailed histories in medical records. The activity of acne was evaluated at 2-year intervals with the use of a 10-point scale: 1 to 3 points indicated mild acne (7.69% of patients), 4 to 6 points indicated moderate acne (24.18%), and 7 to 10 points indicated severe acne (68.13%).

Treatment of Persistent Acne in Adolescence
Treatment was comprised of oral therapy with antibiotics, isotretinoin, and/or application of topical retinoids (sometimes supported with OCPs). Monotherapy was the standard of treatment more than 25 years ago when patients with persistent adult acne were treated as adolescents or young adults. As many as 43.96% of patients with persistent adult acne did not receive any of these therapies before 25 years of age; rather, they used antiacne cosmetics or beauty procedures. Furthermore, 50.55% of patients were treated with oral antibiotics (Figure 2). Topical retinoids were used in 19.78% of patients and isotretinoin was used in 16.48%. Incidentally, OCPs were given to 26.5%. In the course of adolescent acne, 31.87% of patients received 2 to 4 courses of treatment with either antibiotics or retinoids (oral or topical), and 5.49% were treated with 5 or more courses of treatment (Figure 3). The analysis of each treatment revealed that only 1 patient received 4 courses of isotretinoin. Five courses of oral antibiotics were given in 1 patient, and 3 courses of topical retinoids were given in the same patient.

Topical Retinoids
In an analysis of the number of treatments with topical retinoids completed by patients with persistent adult acne, it was established that 80.22% of patients never used topical retinoids for acne during adolescence. Additionally, 12.08% of these patients completed 1 course of treatment, and 7.69% completed 2 to 4 treatments. However, after 25 years of age, only 25.27% of the patients with persistent adult acne were not treated with topical retinoids, and 35.16% completed more than 2 courses of treatment.

Duration of Treatment
Because adult acne is a chronic disease, the mean number of years that patients received treatment over the disease course was analyzed. In the case of persistent adult acne, the mean duration of treatment, including therapy received during adolescence, was more than 13 years. At the time of the study, more than 30% of patients had been undergoing treatment of adult acne for more than 20 years. Scars— The proportion of patients with persistent adult acne who experienced scarring was evaluated. In the persistent adult acne group, scars were identified in 53.85% of patients. Scars appeared only during adolescence in 26.37% of patients with persistent adult acne, scars appeared only after 25 years of age in 21.97% of patients, and scars appeared in adolescence as well as adulthood in 30.77% of patients.

In an analysis of patients with persistent adult acne who experienced scarring after 25 years of age, the proportion of patients with untreated adolescent acne and those who were treated with antibiotics only was not significantly different (60% vs 64%; P = .478)(Table). The inclusion of topical retinoids into treatment decreased the proportion of scars (isotretinoin: 20%, P = .009; topical retinoids: 38.89%, P = .114).

Comment

Persistent Adult Acne
Patients with symptoms of persistent adult acne represented 81.98% of the study population, which was similar to a 1999 study by Goulden et al, ¹ a 2001 study by Shaw and White, ¹³ and a 2009 report by Schmidt et al. ¹⁴ Of these patients with persistent adult acne, 23.08% initiated therapy after 25 years of age, and 23.08% started treatment at least 10 years after acne lesions first appeared. However, it is noteworthy that 68.13% of all patients with persistent adult acne assessed their disease as severe.

Treatment Modalities for Adult Acne
Over the last 5 years, some researchers have attempted to make recommendations for the treatment of adult acne based on standards adopted for the treatment of adolescent acne. ^2,9,15 First-line treatment of patients with adult comedonal acne is topical retinoids. ⁹ The recommended treatment of mild to moderate adult inflammatory acne involves topical drugs, including retinoids, azelaic acid, or benzoyl peroxide, or oral medications, including antibiotics, OCPs, or antiandrogens. In severe inflammatory acne, the recommended treatment involves oral isotretinoin or combined therapies; the latter seems to be the most effective. ¹⁶ Furthermore, this therapy has been adjusted to the patient’s current clinical condition; general individual sensitivity of the skin to irritation and the risk for irritant activity of topical medications; and life situation, such as planned pregnancies and intended use of OCPs due to the risk for teratogenic effects of drugs. ¹⁷

To assess available treatment modalities, oral therapy with antibiotics or isotretinoin as well as topical retinoids were selected for our analysis. It is difficult to determine an exclusive impact of OCPs as acne treatment; according to our study, many female patients use hormone therapy for other medical conditions or contraception, and only a small proportion of these patients are prescribed hormone treatment for acne. We found that 43.96% of patients with persistent adult acne underwent no treatment with antibiotics, isotretinoin, or topical retinoids in adolescence. Patients who did not receive any of these treatments came only for single visits to a dermatologist, did not comply to a recommended therapy, or used only cosmetics or beauty procedures. We found that 80.22% of patients with persistent adult acne never used topical retinoids during adolescence and did not receive maintenance therapy, which may be attributed to the fact that there were no strict recommendations regarding retinoid treatment when these patients were adolescents or young adults. Published data indicate that retinoid use for acne treatment is not common. ¹⁸ Conversely, among patients older than 25 years with late-onset adult acne, there was only 1 patient (ie, < 1%) who had never received any oral antibiotic or isotretinoin treatment or therapy with topical retinoids. The reason for the lack of medical treatment is unknown. Only 25.27% of patients were not treated with topical retinoids, and 35.16% completed at least 2 courses of treatment. The use of topical retinoids for the treatment of persistent and late-onset adult acne may be the result of the spread of knowledge among dermatologists acquired over the last 25 years.

Acne Scarring
The worst complication of acne is scarring. Scars develop for the duration of the disease, during both adolescent and adult acne. In the group with persistent adult acne, scarring was found in 53.85% of patients. Scar formation has been previously reported as a common complication of acne. ¹⁹ The effects of skin lesions that remain after acne are not only limited to impaired cosmetic appearance; they also negatively affect mental health and impair quality of life. ²⁰ The aim of our study was to analyze types of treatment for adolescent acne in patients who later had persistent adult acne. Postacne scars observed later are objective evidence of the severity of disease. We found that using oral antibiotics did not diminish the number of scars among persistent adult acne patients in adulthood. In contrast, isotretinoin or topical retinoid treatment during adolescence decreased the risk for scars occurring during adulthood. In our opinion, these findings emphasize the role of this type of treatment among adolescents or young adults. The decrease of scar formation in adult acne due to retinoid treatment in adolescence indirectly justifies the role of maintenance therapy with topical retinoids. ^21,22

Inflammation is a backdrop to the commonly cited elements of the pathophysiology of acne: Propionibacterium acnes proliferation, increased sebum production with an increase in circulating androgens, and faulty keratinization.^1,2 In fact, research shows that the initiating lesion of acne vulgaris—the microcomedone—is, in essence, an inflammatory lesion.³ This realization has clearly influenced the approach to acne treatment but has not yielded a bevy of new treatments.

A better understanding of acne pathophysiology and the role of inflammation has, however, yielded a better understanding of how existing therapies treat the disease and have led to more comprehensive treatment strategies that are multitargeted. Nonetheless, topical and oral antibiotics remain mainstays of acne therapy, along with topical retinoids and benzoyl peroxide. Current guidelines of care for acne emphasize strategies that reduce dependence on antibiotics and minimize the risk for resistance.⁴ The therapeutic landscape might at last be shifting, with new chemical entities for acne and several novel formulations in development.

Sarecycline: A Novel Tetracycline

Tetracycline antibiotics have been used to manage acne since the 1950s, but their method of action in the disease has not been fully elucidated.⁵ In addition to antibiotic effects, tetracyclines have been shown to confer anti-inflammatory properties and other biologic effects.^6,7

First-generation tetracycline is broad spectrum. As such, it is associated with increased potential for antibiotic resistance and greater impact on gastrointestinal health. The novel compound sarecycline is a tetracycline with a narrower spectrum of activity compared to other tetracyclines and with reduced activity against enteric gram-negative bacteria⁸ (Figure 1). Sarecycline recently was approved by the US Food and Drug Administration (FDA) in a once-daily oral formulation for the treatment of inflammatory lesions of nonnodular moderate to severe acne vulgaris in patients 9 years and older. Sarecycline is dosed at 1.5 mg/kg daily. The FDA approval marks the first new antibiotic approved for acne in 4 decades.

Sarecycline also was assessed in the 2 trials for efficacy in the treatment of back and chest acne; in the active treatment group, IGA success was achieved by 29.6% and 36.6%, respectively, compared to 19.6% and 21.6%, respectively, of controls.⁹

Tazarotene Foam in Focus

Topical tazarotene is commercially available in cream, gel, and foam formulations. Tazarotene foam 0.1% was FDA approved in 2012 for the treatment of acne vulgaris in patients 12 years and older. However, the product was recently relaunched to the market and therefore warrants discussion.

Similar to other retinoids, topical tazarotene has been associated with the potential for application-site irritation. This aqueous foam formulation of tazarotene was designed for ease of application and to attempt to impart moisturizing effects to offset potential irritation. It contains noncomedogenic light mineral oil, which is an emollient. The foam spreads easily, including on hair-bearing skin, with demonstrated penetration of the active drug into the epidermis and dermis. Nonetheless, compared to the gel formulation of tazarotene, the foam formulation was associated with reduced systemic exposure.¹⁰

The tazarotene foam formulation does not contain alcohol, fragrance, propylene glycol, or parabens. Clinical trial participants, blinded to whether they were on active treatment or vehicle foam, consistently rated the foam formulation favorably for ease of application and spreadability, lack of stickiness or residue, and moisturizing effect. The foam vehicle is suggested to increase compliance and satisfaction in some patients.¹¹The efficacy and tolerability of tazarotene foam 0.1% was investigated in 2 randomized, double-blind, vehicle-controlled, parallel-group studies in the United States and Canada.¹² The studies involved participants aged 2 to 45 years who were randomized to receive treatment with either tazarotene foam 0.1% or vehicle foam once daily for 12 weeks (N=1486). Lesion counts, investigator static global assessment, and subject global assessment were evaluated at baseline and at weeks 2, 4, 8, and 12. At week 12, mean reduction from baseline in noninflammatory lesions was 55.9% for active treatment, mean reduction in inflammatory lesions was 56.1%, and mean total lesion reduction was 56% compared to mean reductions of 37.7%, 45.3%, and 40.8%, respectively, for vehicle. In all, 28.2% of participants achieved treatment success with active treatment compared to 14.7% of controls. There was a greater proportion of active-treatment participants with investigator static global assessment scores of 0 or 1 compared to vehicle. The only adverse events reported by more than 5% of participants in the active-treatment groups in both studies were application-site skin irritation and dryness.¹²

Topical Minocycline

Systemic minocycline is the most commonly prescribed oral antibiotic for acne management.¹³ Despite its widespread use, it is not without potential safety concerns. Minocycline is distinct among tetracyclines for posing a small risk for systemic lupus erythematosus and autoimmune TEAE.Gastrointestinal side effects and bluish discoloration also are reported.¹⁴ Topical application of minocycline for acne would optimize the therapeutic effect while reducing systemic effects. FMX101 4%, an investigational minocycline foam, is being studied for the treatment of moderate to severe acne.

In a pharmacokinetic study, minocycline exposure was 730- to 765-times lower with foam application vs oral minocycline.¹⁵ No evidence of minocycline accumulation was identified over the 21 days of application of minocycline foam 4%. Minocycline foam 4% appeared to be safe and well tolerated, without serious TEAEs, treatment-related TEAEs, or TEAEs that led to treatment discontinuation.¹⁵

In 2 identical phase 3 studies in which 961 participants were randomized (2:1) to once-daily minocycline foam 4% or foam vehicle for 12 weeks, participants in the active-treatment group demonstrated a significantly greater reduction in both inflammatory and noninflammatory lesions in both studies (both P<.05) and a greater rate of treatment success (≥2 point reduction in IGA and score of 0 [clear] or 1 [almost clear]) in 1 study. Treatment was generally safe and well tolerated, with skin-related adverse events reported in fewer than 1% of participants receiving active treatment.¹⁶

In an open-label safety extension study that enrolled 657 patients, treatment with FMX101 continued for as long as 40 weeks.¹⁷ In total, 291 participants completed 52 weeks of therapy. Rates and types of reported TEAEs in the open-label extension phase were similar to those seen in the phase 3 trials. Application-site TEAEs occurred in fewer than 2% of participants. Participants reported a high level of treatment satisfaction at week 52.¹⁷

In a more recent phase 3 study, 1507 participants were randomized (1:1) to once-daily minocycline foam 4% or foam vehicle for 12 weeks to further evaluate the efficacy and safety of FMX101 4% for moderate to severe acne vulgaris.¹⁸ The study met both primary end points: absolute change from baseline in the inflammatory lesion count (−16.93 vs −13.40; P<.0001) and the noninflammatory lesion count (−18.80 vs −15.89; P<.05), as well as percentage of participants with IGA treatment success at week 12 (30.80% vs 19.63%; P<.0001). The percentage reduction in the inflammatory lesion count was statistically significantly greater for minocycline foam 4% compared to vehicle as early as week 3 (P<.0001). The safety profile was found to be consistent with the 2 earlier phase 3 studies.¹⁸

Topical Minocycline in Rosacea

A similar foam formulation of minocycline (1.5% concentration) has shown benefit in 2 identical phase 3 studies.¹⁹ A total of 1522 participants were enrolled in 2 phase 3, randomized, multicenter, double-blind, vehicle-controlled, 2-arm studies in participants 18 years and older with moderate to severe papulopustular rosacea. Participants were randomized (2:1) to either minocycline foam 1.5% or vehicle once daily to the face for 12 weeks.¹⁹

Treatment was associated with a statistically significant reduction in counts of inflammatory lesions of rosacea (Study FX2016-11: −17.57 vs −15.65 [P=.003]; Study FX2016-12: −18.54 vs −14.88 [P<.0001]) and a significantly higher rate of IGA treatment success compared to vehicle (Study FX2016-11: 52.1% vs 43.0% [P=.027]; Study FX2016-12: 49.1% vs 39.0% [P=.008]), highlighting the anti-inflammatory action of the topically applied agent.¹⁹

The most common TEAE for both studies was upper respiratory tract infection; there were no serious TEAEs. Overall, 9 participants across both studies discontinued because of a TEAE (foam, 7 participants; vehicle, 2 participants).¹⁹

Clascoterone: First-in-Class Topical

Clascoterone cream 1% is a new chemical entity under investigation for the treatment of moderate to severe acne in patients 9 years and older. Clascoterone targets androgen receptors in the skin to block the effects of circulating endogenous androgens; chemically, it shares a 4-ring backbone identical to dihydrotestosterone and spironolactone (Figure 2). Clascoterone competes with dihydrotestosterone for binding to the androgen receptor to limit or block transcription of androgen-responsive genes and modify specific gene expression.²⁰

Androgens are known to promote both sebum production and inflammatory responses within the follicle, contributing to the cycle of acne.²¹ Antiandrogen therapy would, therefore, inhibit excess sebum production and directly reduce the presence of certain inflammatory mediators in skin. This effect is expected to lead to reduced follicular plugging and a reduction in growth of P acnes and its inflammatory by-products.

Direct and indirect hormonal modulation have been successfully employed to manage acne in women; however, such therapies have not been considered first-line interventions for the disease.²² Although systemic antiandrogens and hormonal modulation are effective for certain women with acne, there may be concerns about systemic exposure²³; no hormone-modulating agent has been adopted for use in men with acne.

As an androgen inhibitor, clascoterone is thought to displace androgen hormones from androgen receptors located at the sebaceous gland and hair follicle, thus inhibiting the cycle of physiologic events that leads to acne formation. Clascoterone is applied topically and acts locally on androgen receptors in the skin, with no systemic exposure seen. In phase 2 trials, clascoterone was found to be safe and effective with no systemic exposure and was suggested to have better tolerability than topical tretinoin.

Preliminary individual study analysis of data from 2 phase 3 trials showed that topical clascoterone met its primary end points, achieving statistically significantly greater rates of IGA treatment success (≥2 point reduction in IGA and score of 0 [clear] or 1 [almost clear]) at week 12 (P<.0001).²⁴ Rates of treatment success for actively treated participants were 16.1% and 18.7%, respectively, compared to 7% and 4.7%, respectively, for vehicle. The study population included both males and nonpregnant females 9 years and older who had a baseline IGA score of 3 (moderate) or 4 (severe). At baseline, participants had a mix of inflammatory lesions (≥30, to a maximum of 75) and noninflammatory lesions (≥30, to a maximum of 100).²⁴

Intention-to-treat analysis at week 12 showed a mean total lesion reduction from baseline for active treatment of 37.1% and 37.7%, respectively, compared to 28.5% and 22.2%, respectively, for controls.²⁴ Mean reductions from baseline in noninflammatory lesions for active treatment were 30.7% and 29.3%, respectively, compared to 21.9% and 15.8%, respectively, for controls. Mean reductions from baseline in inflammatory lesions for active treatment were 44.8% and 47%, respectively, compared to 36.6% and 29.8%, respectively, for controls. Similarly low rates of TEAEs were reported in active and placebo groups in both studies. No TEAE suggested systemic antiandrogen exposure.²⁴

Advancements in Cannabinoids

Advancements in pharmaceutical development of cannabinoid compounds have largely coincided with the controversial national movement to legalize medical marijuana and decriminalize recreational marijuana use. Despite the temporal connection, the 2 topics are entirely distinct. Importantly, pharmaceutical development is largely focused on the effects of cannabidiol (CBD), which is 1 of approximately 113 cannabinoids identified from Cannabis sativa. Cannabidiol is not tetrahydrocannabinol, or THC, the compound responsible for marijuana’s psychoactive effects and addictive properties; CBD does not have any psychoactive effects and is not addictive (Figure 3).²⁵

A CBD oral solution agent recently gained FDA approval for seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients 2 years and older; it is estimated that more than 180 trials of CBD are ongoing in the United States for various indications.²⁶ A notable question in the development of CBD-based therapies is: What is the role of natural plant-derived CBD compared to a pure synthetic form of CBD? The latter is akin to a pharmaceutical process in which a single molecule is developed as the active drug.²⁷ Although the potency and composition of plant-derived CBD can vary with crop conditions, plant strains, and the extraction process, a synthetic molecule would allow for consistency in safety, potency, and pharmacokinetic properties, as well as efficacy, as a consequence.²⁶

There are intriguing data to suggest a potential use for topical CBD in the management of skin diseases, including acne vulgaris. Researchers have, for at least a decade, been investigating the role of the endocannabinoid system, which has physiologic regulatory functions in proliferation, differentiation, apoptosis and cytokine, mediator, and hormone production of various cell types in skin, hair follicles, and sebaceous glands.²⁸ Cannabidiol has been shown to suppress proliferation of sebocytes through activation of transient receptor potential vanilloid 4 ion channels and to have anti-inflammatory effects on sebocytes.²⁹ It has been shown to inhibit human keratinocyte proliferation through a non-CB1/CB2 mechanism³⁰ and to possess potent antimicrobial activity against gram-positive bacteria such as P acnes.³¹

Given these effects on sebocytes, modulation of keratinocyte proliferation, and anti-inflammatory and antibacterial effects, CBD could prove beneficial in the management of acne vulgaris. A new synthetic CBD topical formulation, BTX 1503, is under investigation for the treatment of acne vulgaris.

Early clinical data confirm both the anti-inflammatory effects of topical BTX 1503 as well as its effects on noninflammatory lesions, with 4-week reductions in inflammatory lesion counts similar to what are reported in clinical trials for leading FDA-approved topical therapies in the same time frame.

The phase 1b trial was a 4-week, open-label study in participants with moderate to severe acne vulgaris.³² The primary end point was safety, as demonstrated by the incidence of TEAE, laboratory monitoring, and assessment of cutaneous tolerability. Exploratory end points included changes in inflammatory and noninflammatory lesion counts and IGA score. A total of 21 participants aged 18 to 65 years with moderate to severe acne vulgaris were enrolled. BTX 1503 was applied topically twice daily. At baseline, eligible participants had 20 to 50 inflammatory lesions and 20 to 100 noninflammatory acne lesions on the face, an IGA of 3 (moderate) or 4 (severe), and 3 or fewer nodular or cystic lesions (>5 mm in diameter). No serious or severe TEAEs were reported; no participants withdrew due to a TEAE. Slight erythema, slight scaling, slight dryness, and slight burning and stinging were reported; there were no reports of irritant or allergic contact dermatitis. Only 1 TEAE was thought to be possibly related to treatment: mild pain at the application site.³²

In addition to presenting a potential new chemical entity for the topical treatment of acne, the novel topical vehicle formulation of BTX 1503 represents an innovative approach to drug delivery. The formulation utilizes proprietary technology to deliver high doses of drug into the skin without controversial penetration enhancers, preservatives, or other potential irritating additives. Instead, volatile excipients are used that evaporate upon application to the skin, leaving a so-called superconcentrated secondary formulation on the skin. The concentration gradient effect then drives the concentrated drug into skin. Although the formulation efficiently delivers active drug into the skin and its appendages, systemic exposure has been reported to be very low. A phase 2 randomized, double-blind, vehicle-controlled trial ongoing in the United States and Australia in 360 patients with moderate to severe acne vulgaris will provide key data to confirm the efficacy and safety of BTX 1503 (ClinicalTrials.gov Identifier NCT03573518).

Conclusion

Drug development continues to focus on the challenge of treating acne effectively and safely. Vehicle innovations are optimizing existing active drugs and creating opportunities to deliver new compounds to the skin. The approval of sarecycline as the first new chemical entity approved for acne in several years may be followed in coming years by other new actives, including clascoterone and CBD.

Inflammation is a backdrop to the commonly cited elements of the pathophysiology of acne: Propionibacterium acnes proliferation, increased sebum production with an increase in circulating androgens, and faulty keratinization.^1,2 In fact, research shows that the initiating lesion of acne vulgaris—the microcomedone—is, in essence, an inflammatory lesion.³ This realization has clearly influenced the approach to acne treatment but has not yielded a bevy of new treatments.

A better understanding of acne pathophysiology and the role of inflammation has, however, yielded a better understanding of how existing therapies treat the disease and have led to more comprehensive treatment strategies that are multitargeted. Nonetheless, topical and oral antibiotics remain mainstays of acne therapy, along with topical retinoids and benzoyl peroxide. Current guidelines of care for acne emphasize strategies that reduce dependence on antibiotics and minimize the risk for resistance.⁴ The therapeutic landscape might at last be shifting, with new chemical entities for acne and several novel formulations in development.

Sarecycline: A Novel Tetracycline

Tetracycline antibiotics have been used to manage acne since the 1950s, but their method of action in the disease has not been fully elucidated.⁵ In addition to antibiotic effects, tetracyclines have been shown to confer anti-inflammatory properties and other biologic effects.^6,7

First-generation tetracycline is broad spectrum. As such, it is associated with increased potential for antibiotic resistance and greater impact on gastrointestinal health. The novel compound sarecycline is a tetracycline with a narrower spectrum of activity compared to other tetracyclines and with reduced activity against enteric gram-negative bacteria⁸ (Figure 1). Sarecycline recently was approved by the US Food and Drug Administration (FDA) in a once-daily oral formulation for the treatment of inflammatory lesions of nonnodular moderate to severe acne vulgaris in patients 9 years and older. Sarecycline is dosed at 1.5 mg/kg daily. The FDA approval marks the first new antibiotic approved for acne in 4 decades.

Sarecycline also was assessed in the 2 trials for efficacy in the treatment of back and chest acne; in the active treatment group, IGA success was achieved by 29.6% and 36.6%, respectively, compared to 19.6% and 21.6%, respectively, of controls.⁹

Tazarotene Foam in Focus

Topical tazarotene is commercially available in cream, gel, and foam formulations. Tazarotene foam 0.1% was FDA approved in 2012 for the treatment of acne vulgaris in patients 12 years and older. However, the product was recently relaunched to the market and therefore warrants discussion.

Similar to other retinoids, topical tazarotene has been associated with the potential for application-site irritation. This aqueous foam formulation of tazarotene was designed for ease of application and to attempt to impart moisturizing effects to offset potential irritation. It contains noncomedogenic light mineral oil, which is an emollient. The foam spreads easily, including on hair-bearing skin, with demonstrated penetration of the active drug into the epidermis and dermis. Nonetheless, compared to the gel formulation of tazarotene, the foam formulation was associated with reduced systemic exposure.¹⁰

The tazarotene foam formulation does not contain alcohol, fragrance, propylene glycol, or parabens. Clinical trial participants, blinded to whether they were on active treatment or vehicle foam, consistently rated the foam formulation favorably for ease of application and spreadability, lack of stickiness or residue, and moisturizing effect. The foam vehicle is suggested to increase compliance and satisfaction in some patients.¹¹The efficacy and tolerability of tazarotene foam 0.1% was investigated in 2 randomized, double-blind, vehicle-controlled, parallel-group studies in the United States and Canada.¹² The studies involved participants aged 2 to 45 years who were randomized to receive treatment with either tazarotene foam 0.1% or vehicle foam once daily for 12 weeks (N=1486). Lesion counts, investigator static global assessment, and subject global assessment were evaluated at baseline and at weeks 2, 4, 8, and 12. At week 12, mean reduction from baseline in noninflammatory lesions was 55.9% for active treatment, mean reduction in inflammatory lesions was 56.1%, and mean total lesion reduction was 56% compared to mean reductions of 37.7%, 45.3%, and 40.8%, respectively, for vehicle. In all, 28.2% of participants achieved treatment success with active treatment compared to 14.7% of controls. There was a greater proportion of active-treatment participants with investigator static global assessment scores of 0 or 1 compared to vehicle. The only adverse events reported by more than 5% of participants in the active-treatment groups in both studies were application-site skin irritation and dryness.¹²

Topical Minocycline

Systemic minocycline is the most commonly prescribed oral antibiotic for acne management.¹³ Despite its widespread use, it is not without potential safety concerns. Minocycline is distinct among tetracyclines for posing a small risk for systemic lupus erythematosus and autoimmune TEAE.Gastrointestinal side effects and bluish discoloration also are reported.¹⁴ Topical application of minocycline for acne would optimize the therapeutic effect while reducing systemic effects. FMX101 4%, an investigational minocycline foam, is being studied for the treatment of moderate to severe acne.

In a pharmacokinetic study, minocycline exposure was 730- to 765-times lower with foam application vs oral minocycline.¹⁵ No evidence of minocycline accumulation was identified over the 21 days of application of minocycline foam 4%. Minocycline foam 4% appeared to be safe and well tolerated, without serious TEAEs, treatment-related TEAEs, or TEAEs that led to treatment discontinuation.¹⁵

In 2 identical phase 3 studies in which 961 participants were randomized (2:1) to once-daily minocycline foam 4% or foam vehicle for 12 weeks, participants in the active-treatment group demonstrated a significantly greater reduction in both inflammatory and noninflammatory lesions in both studies (both P<.05) and a greater rate of treatment success (≥2 point reduction in IGA and score of 0 [clear] or 1 [almost clear]) in 1 study. Treatment was generally safe and well tolerated, with skin-related adverse events reported in fewer than 1% of participants receiving active treatment.¹⁶

In an open-label safety extension study that enrolled 657 patients, treatment with FMX101 continued for as long as 40 weeks.¹⁷ In total, 291 participants completed 52 weeks of therapy. Rates and types of reported TEAEs in the open-label extension phase were similar to those seen in the phase 3 trials. Application-site TEAEs occurred in fewer than 2% of participants. Participants reported a high level of treatment satisfaction at week 52.¹⁷

In a more recent phase 3 study, 1507 participants were randomized (1:1) to once-daily minocycline foam 4% or foam vehicle for 12 weeks to further evaluate the efficacy and safety of FMX101 4% for moderate to severe acne vulgaris.¹⁸ The study met both primary end points: absolute change from baseline in the inflammatory lesion count (−16.93 vs −13.40; P<.0001) and the noninflammatory lesion count (−18.80 vs −15.89; P<.05), as well as percentage of participants with IGA treatment success at week 12 (30.80% vs 19.63%; P<.0001). The percentage reduction in the inflammatory lesion count was statistically significantly greater for minocycline foam 4% compared to vehicle as early as week 3 (P<.0001). The safety profile was found to be consistent with the 2 earlier phase 3 studies.¹⁸

Topical Minocycline in Rosacea

A similar foam formulation of minocycline (1.5% concentration) has shown benefit in 2 identical phase 3 studies.¹⁹ A total of 1522 participants were enrolled in 2 phase 3, randomized, multicenter, double-blind, vehicle-controlled, 2-arm studies in participants 18 years and older with moderate to severe papulopustular rosacea. Participants were randomized (2:1) to either minocycline foam 1.5% or vehicle once daily to the face for 12 weeks.¹⁹

Treatment was associated with a statistically significant reduction in counts of inflammatory lesions of rosacea (Study FX2016-11: −17.57 vs −15.65 [P=.003]; Study FX2016-12: −18.54 vs −14.88 [P<.0001]) and a significantly higher rate of IGA treatment success compared to vehicle (Study FX2016-11: 52.1% vs 43.0% [P=.027]; Study FX2016-12: 49.1% vs 39.0% [P=.008]), highlighting the anti-inflammatory action of the topically applied agent.¹⁹

The most common TEAE for both studies was upper respiratory tract infection; there were no serious TEAEs. Overall, 9 participants across both studies discontinued because of a TEAE (foam, 7 participants; vehicle, 2 participants).¹⁹

Clascoterone: First-in-Class Topical

Clascoterone cream 1% is a new chemical entity under investigation for the treatment of moderate to severe acne in patients 9 years and older. Clascoterone targets androgen receptors in the skin to block the effects of circulating endogenous androgens; chemically, it shares a 4-ring backbone identical to dihydrotestosterone and spironolactone (Figure 2). Clascoterone competes with dihydrotestosterone for binding to the androgen receptor to limit or block transcription of androgen-responsive genes and modify specific gene expression.²⁰

Androgens are known to promote both sebum production and inflammatory responses within the follicle, contributing to the cycle of acne.²¹ Antiandrogen therapy would, therefore, inhibit excess sebum production and directly reduce the presence of certain inflammatory mediators in skin. This effect is expected to lead to reduced follicular plugging and a reduction in growth of P acnes and its inflammatory by-products.

Direct and indirect hormonal modulation have been successfully employed to manage acne in women; however, such therapies have not been considered first-line interventions for the disease.²² Although systemic antiandrogens and hormonal modulation are effective for certain women with acne, there may be concerns about systemic exposure²³; no hormone-modulating agent has been adopted for use in men with acne.

As an androgen inhibitor, clascoterone is thought to displace androgen hormones from androgen receptors located at the sebaceous gland and hair follicle, thus inhibiting the cycle of physiologic events that leads to acne formation. Clascoterone is applied topically and acts locally on androgen receptors in the skin, with no systemic exposure seen. In phase 2 trials, clascoterone was found to be safe and effective with no systemic exposure and was suggested to have better tolerability than topical tretinoin.

Preliminary individual study analysis of data from 2 phase 3 trials showed that topical clascoterone met its primary end points, achieving statistically significantly greater rates of IGA treatment success (≥2 point reduction in IGA and score of 0 [clear] or 1 [almost clear]) at week 12 (P<.0001).²⁴ Rates of treatment success for actively treated participants were 16.1% and 18.7%, respectively, compared to 7% and 4.7%, respectively, for vehicle. The study population included both males and nonpregnant females 9 years and older who had a baseline IGA score of 3 (moderate) or 4 (severe). At baseline, participants had a mix of inflammatory lesions (≥30, to a maximum of 75) and noninflammatory lesions (≥30, to a maximum of 100).²⁴

Intention-to-treat analysis at week 12 showed a mean total lesion reduction from baseline for active treatment of 37.1% and 37.7%, respectively, compared to 28.5% and 22.2%, respectively, for controls.²⁴ Mean reductions from baseline in noninflammatory lesions for active treatment were 30.7% and 29.3%, respectively, compared to 21.9% and 15.8%, respectively, for controls. Mean reductions from baseline in inflammatory lesions for active treatment were 44.8% and 47%, respectively, compared to 36.6% and 29.8%, respectively, for controls. Similarly low rates of TEAEs were reported in active and placebo groups in both studies. No TEAE suggested systemic antiandrogen exposure.²⁴

Advancements in Cannabinoids

Advancements in pharmaceutical development of cannabinoid compounds have largely coincided with the controversial national movement to legalize medical marijuana and decriminalize recreational marijuana use. Despite the temporal connection, the 2 topics are entirely distinct. Importantly, pharmaceutical development is largely focused on the effects of cannabidiol (CBD), which is 1 of approximately 113 cannabinoids identified from Cannabis sativa. Cannabidiol is not tetrahydrocannabinol, or THC, the compound responsible for marijuana’s psychoactive effects and addictive properties; CBD does not have any psychoactive effects and is not addictive (Figure 3).²⁵

A CBD oral solution agent recently gained FDA approval for seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients 2 years and older; it is estimated that more than 180 trials of CBD are ongoing in the United States for various indications.²⁶ A notable question in the development of CBD-based therapies is: What is the role of natural plant-derived CBD compared to a pure synthetic form of CBD? The latter is akin to a pharmaceutical process in which a single molecule is developed as the active drug.²⁷ Although the potency and composition of plant-derived CBD can vary with crop conditions, plant strains, and the extraction process, a synthetic molecule would allow for consistency in safety, potency, and pharmacokinetic properties, as well as efficacy, as a consequence.²⁶

There are intriguing data to suggest a potential use for topical CBD in the management of skin diseases, including acne vulgaris. Researchers have, for at least a decade, been investigating the role of the endocannabinoid system, which has physiologic regulatory functions in proliferation, differentiation, apoptosis and cytokine, mediator, and hormone production of various cell types in skin, hair follicles, and sebaceous glands.²⁸ Cannabidiol has been shown to suppress proliferation of sebocytes through activation of transient receptor potential vanilloid 4 ion channels and to have anti-inflammatory effects on sebocytes.²⁹ It has been shown to inhibit human keratinocyte proliferation through a non-CB1/CB2 mechanism³⁰ and to possess potent antimicrobial activity against gram-positive bacteria such as P acnes.³¹

Given these effects on sebocytes, modulation of keratinocyte proliferation, and anti-inflammatory and antibacterial effects, CBD could prove beneficial in the management of acne vulgaris. A new synthetic CBD topical formulation, BTX 1503, is under investigation for the treatment of acne vulgaris.

Early clinical data confirm both the anti-inflammatory effects of topical BTX 1503 as well as its effects on noninflammatory lesions, with 4-week reductions in inflammatory lesion counts similar to what are reported in clinical trials for leading FDA-approved topical therapies in the same time frame.

The phase 1b trial was a 4-week, open-label study in participants with moderate to severe acne vulgaris.³² The primary end point was safety, as demonstrated by the incidence of TEAE, laboratory monitoring, and assessment of cutaneous tolerability. Exploratory end points included changes in inflammatory and noninflammatory lesion counts and IGA score. A total of 21 participants aged 18 to 65 years with moderate to severe acne vulgaris were enrolled. BTX 1503 was applied topically twice daily. At baseline, eligible participants had 20 to 50 inflammatory lesions and 20 to 100 noninflammatory acne lesions on the face, an IGA of 3 (moderate) or 4 (severe), and 3 or fewer nodular or cystic lesions (>5 mm in diameter). No serious or severe TEAEs were reported; no participants withdrew due to a TEAE. Slight erythema, slight scaling, slight dryness, and slight burning and stinging were reported; there were no reports of irritant or allergic contact dermatitis. Only 1 TEAE was thought to be possibly related to treatment: mild pain at the application site.³²

In addition to presenting a potential new chemical entity for the topical treatment of acne, the novel topical vehicle formulation of BTX 1503 represents an innovative approach to drug delivery. The formulation utilizes proprietary technology to deliver high doses of drug into the skin without controversial penetration enhancers, preservatives, or other potential irritating additives. Instead, volatile excipients are used that evaporate upon application to the skin, leaving a so-called superconcentrated secondary formulation on the skin. The concentration gradient effect then drives the concentrated drug into skin. Although the formulation efficiently delivers active drug into the skin and its appendages, systemic exposure has been reported to be very low. A phase 2 randomized, double-blind, vehicle-controlled trial ongoing in the United States and Australia in 360 patients with moderate to severe acne vulgaris will provide key data to confirm the efficacy and safety of BTX 1503 (ClinicalTrials.gov Identifier NCT03573518).

Conclusion

Drug development continues to focus on the challenge of treating acne effectively and safely. Vehicle innovations are optimizing existing active drugs and creating opportunities to deliver new compounds to the skin. The approval of sarecycline as the first new chemical entity approved for acne in several years may be followed in coming years by other new actives, including clascoterone and CBD.

Inflammation is a backdrop to the commonly cited elements of the pathophysiology of acne: Propionibacterium acnes proliferation, increased sebum production with an increase in circulating androgens, and faulty keratinization.^1,2 In fact, research shows that the initiating lesion of acne vulgaris—the microcomedone—is, in essence, an inflammatory lesion.³ This realization has clearly influenced the approach to acne treatment but has not yielded a bevy of new treatments.

A better understanding of acne pathophysiology and the role of inflammation has, however, yielded a better understanding of how existing therapies treat the disease and have led to more comprehensive treatment strategies that are multitargeted. Nonetheless, topical and oral antibiotics remain mainstays of acne therapy, along with topical retinoids and benzoyl peroxide. Current guidelines of care for acne emphasize strategies that reduce dependence on antibiotics and minimize the risk for resistance.⁴ The therapeutic landscape might at last be shifting, with new chemical entities for acne and several novel formulations in development.

Sarecycline: A Novel Tetracycline

Tetracycline antibiotics have been used to manage acne since the 1950s, but their method of action in the disease has not been fully elucidated.⁵ In addition to antibiotic effects, tetracyclines have been shown to confer anti-inflammatory properties and other biologic effects.^6,7

First-generation tetracycline is broad spectrum. As such, it is associated with increased potential for antibiotic resistance and greater impact on gastrointestinal health. The novel compound sarecycline is a tetracycline with a narrower spectrum of activity compared to other tetracyclines and with reduced activity against enteric gram-negative bacteria⁸ (Figure 1). Sarecycline recently was approved by the US Food and Drug Administration (FDA) in a once-daily oral formulation for the treatment of inflammatory lesions of nonnodular moderate to severe acne vulgaris in patients 9 years and older. Sarecycline is dosed at 1.5 mg/kg daily. The FDA approval marks the first new antibiotic approved for acne in 4 decades.

Sarecycline also was assessed in the 2 trials for efficacy in the treatment of back and chest acne; in the active treatment group, IGA success was achieved by 29.6% and 36.6%, respectively, compared to 19.6% and 21.6%, respectively, of controls.⁹

Tazarotene Foam in Focus

Topical tazarotene is commercially available in cream, gel, and foam formulations. Tazarotene foam 0.1% was FDA approved in 2012 for the treatment of acne vulgaris in patients 12 years and older. However, the product was recently relaunched to the market and therefore warrants discussion.

Similar to other retinoids, topical tazarotene has been associated with the potential for application-site irritation. This aqueous foam formulation of tazarotene was designed for ease of application and to attempt to impart moisturizing effects to offset potential irritation. It contains noncomedogenic light mineral oil, which is an emollient. The foam spreads easily, including on hair-bearing skin, with demonstrated penetration of the active drug into the epidermis and dermis. Nonetheless, compared to the gel formulation of tazarotene, the foam formulation was associated with reduced systemic exposure.¹⁰

The tazarotene foam formulation does not contain alcohol, fragrance, propylene glycol, or parabens. Clinical trial participants, blinded to whether they were on active treatment or vehicle foam, consistently rated the foam formulation favorably for ease of application and spreadability, lack of stickiness or residue, and moisturizing effect. The foam vehicle is suggested to increase compliance and satisfaction in some patients.¹¹The efficacy and tolerability of tazarotene foam 0.1% was investigated in 2 randomized, double-blind, vehicle-controlled, parallel-group studies in the United States and Canada.¹² The studies involved participants aged 2 to 45 years who were randomized to receive treatment with either tazarotene foam 0.1% or vehicle foam once daily for 12 weeks (N=1486). Lesion counts, investigator static global assessment, and subject global assessment were evaluated at baseline and at weeks 2, 4, 8, and 12. At week 12, mean reduction from baseline in noninflammatory lesions was 55.9% for active treatment, mean reduction in inflammatory lesions was 56.1%, and mean total lesion reduction was 56% compared to mean reductions of 37.7%, 45.3%, and 40.8%, respectively, for vehicle. In all, 28.2% of participants achieved treatment success with active treatment compared to 14.7% of controls. There was a greater proportion of active-treatment participants with investigator static global assessment scores of 0 or 1 compared to vehicle. The only adverse events reported by more than 5% of participants in the active-treatment groups in both studies were application-site skin irritation and dryness.¹²

Topical Minocycline

Systemic minocycline is the most commonly prescribed oral antibiotic for acne management.¹³ Despite its widespread use, it is not without potential safety concerns. Minocycline is distinct among tetracyclines for posing a small risk for systemic lupus erythematosus and autoimmune TEAE.Gastrointestinal side effects and bluish discoloration also are reported.¹⁴ Topical application of minocycline for acne would optimize the therapeutic effect while reducing systemic effects. FMX101 4%, an investigational minocycline foam, is being studied for the treatment of moderate to severe acne.

In a pharmacokinetic study, minocycline exposure was 730- to 765-times lower with foam application vs oral minocycline.¹⁵ No evidence of minocycline accumulation was identified over the 21 days of application of minocycline foam 4%. Minocycline foam 4% appeared to be safe and well tolerated, without serious TEAEs, treatment-related TEAEs, or TEAEs that led to treatment discontinuation.¹⁵

In 2 identical phase 3 studies in which 961 participants were randomized (2:1) to once-daily minocycline foam 4% or foam vehicle for 12 weeks, participants in the active-treatment group demonstrated a significantly greater reduction in both inflammatory and noninflammatory lesions in both studies (both P<.05) and a greater rate of treatment success (≥2 point reduction in IGA and score of 0 [clear] or 1 [almost clear]) in 1 study. Treatment was generally safe and well tolerated, with skin-related adverse events reported in fewer than 1% of participants receiving active treatment.¹⁶

In an open-label safety extension study that enrolled 657 patients, treatment with FMX101 continued for as long as 40 weeks.¹⁷ In total, 291 participants completed 52 weeks of therapy. Rates and types of reported TEAEs in the open-label extension phase were similar to those seen in the phase 3 trials. Application-site TEAEs occurred in fewer than 2% of participants. Participants reported a high level of treatment satisfaction at week 52.¹⁷

In a more recent phase 3 study, 1507 participants were randomized (1:1) to once-daily minocycline foam 4% or foam vehicle for 12 weeks to further evaluate the efficacy and safety of FMX101 4% for moderate to severe acne vulgaris.¹⁸ The study met both primary end points: absolute change from baseline in the inflammatory lesion count (−16.93 vs −13.40; P<.0001) and the noninflammatory lesion count (−18.80 vs −15.89; P<.05), as well as percentage of participants with IGA treatment success at week 12 (30.80% vs 19.63%; P<.0001). The percentage reduction in the inflammatory lesion count was statistically significantly greater for minocycline foam 4% compared to vehicle as early as week 3 (P<.0001). The safety profile was found to be consistent with the 2 earlier phase 3 studies.¹⁸

Topical Minocycline in Rosacea

A similar foam formulation of minocycline (1.5% concentration) has shown benefit in 2 identical phase 3 studies.¹⁹ A total of 1522 participants were enrolled in 2 phase 3, randomized, multicenter, double-blind, vehicle-controlled, 2-arm studies in participants 18 years and older with moderate to severe papulopustular rosacea. Participants were randomized (2:1) to either minocycline foam 1.5% or vehicle once daily to the face for 12 weeks.¹⁹

Treatment was associated with a statistically significant reduction in counts of inflammatory lesions of rosacea (Study FX2016-11: −17.57 vs −15.65 [P=.003]; Study FX2016-12: −18.54 vs −14.88 [P<.0001]) and a significantly higher rate of IGA treatment success compared to vehicle (Study FX2016-11: 52.1% vs 43.0% [P=.027]; Study FX2016-12: 49.1% vs 39.0% [P=.008]), highlighting the anti-inflammatory action of the topically applied agent.¹⁹

The most common TEAE for both studies was upper respiratory tract infection; there were no serious TEAEs. Overall, 9 participants across both studies discontinued because of a TEAE (foam, 7 participants; vehicle, 2 participants).¹⁹

Clascoterone: First-in-Class Topical

Clascoterone cream 1% is a new chemical entity under investigation for the treatment of moderate to severe acne in patients 9 years and older. Clascoterone targets androgen receptors in the skin to block the effects of circulating endogenous androgens; chemically, it shares a 4-ring backbone identical to dihydrotestosterone and spironolactone (Figure 2). Clascoterone competes with dihydrotestosterone for binding to the androgen receptor to limit or block transcription of androgen-responsive genes and modify specific gene expression.²⁰

Androgens are known to promote both sebum production and inflammatory responses within the follicle, contributing to the cycle of acne.²¹ Antiandrogen therapy would, therefore, inhibit excess sebum production and directly reduce the presence of certain inflammatory mediators in skin. This effect is expected to lead to reduced follicular plugging and a reduction in growth of P acnes and its inflammatory by-products.

Direct and indirect hormonal modulation have been successfully employed to manage acne in women; however, such therapies have not been considered first-line interventions for the disease.²² Although systemic antiandrogens and hormonal modulation are effective for certain women with acne, there may be concerns about systemic exposure²³; no hormone-modulating agent has been adopted for use in men with acne.

As an androgen inhibitor, clascoterone is thought to displace androgen hormones from androgen receptors located at the sebaceous gland and hair follicle, thus inhibiting the cycle of physiologic events that leads to acne formation. Clascoterone is applied topically and acts locally on androgen receptors in the skin, with no systemic exposure seen. In phase 2 trials, clascoterone was found to be safe and effective with no systemic exposure and was suggested to have better tolerability than topical tretinoin.

Preliminary individual study analysis of data from 2 phase 3 trials showed that topical clascoterone met its primary end points, achieving statistically significantly greater rates of IGA treatment success (≥2 point reduction in IGA and score of 0 [clear] or 1 [almost clear]) at week 12 (P<.0001).²⁴ Rates of treatment success for actively treated participants were 16.1% and 18.7%, respectively, compared to 7% and 4.7%, respectively, for vehicle. The study population included both males and nonpregnant females 9 years and older who had a baseline IGA score of 3 (moderate) or 4 (severe). At baseline, participants had a mix of inflammatory lesions (≥30, to a maximum of 75) and noninflammatory lesions (≥30, to a maximum of 100).²⁴

Intention-to-treat analysis at week 12 showed a mean total lesion reduction from baseline for active treatment of 37.1% and 37.7%, respectively, compared to 28.5% and 22.2%, respectively, for controls.²⁴ Mean reductions from baseline in noninflammatory lesions for active treatment were 30.7% and 29.3%, respectively, compared to 21.9% and 15.8%, respectively, for controls. Mean reductions from baseline in inflammatory lesions for active treatment were 44.8% and 47%, respectively, compared to 36.6% and 29.8%, respectively, for controls. Similarly low rates of TEAEs were reported in active and placebo groups in both studies. No TEAE suggested systemic antiandrogen exposure.²⁴

Advancements in Cannabinoids

Advancements in pharmaceutical development of cannabinoid compounds have largely coincided with the controversial national movement to legalize medical marijuana and decriminalize recreational marijuana use. Despite the temporal connection, the 2 topics are entirely distinct. Importantly, pharmaceutical development is largely focused on the effects of cannabidiol (CBD), which is 1 of approximately 113 cannabinoids identified from Cannabis sativa. Cannabidiol is not tetrahydrocannabinol, or THC, the compound responsible for marijuana’s psychoactive effects and addictive properties; CBD does not have any psychoactive effects and is not addictive (Figure 3).²⁵

A CBD oral solution agent recently gained FDA approval for seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients 2 years and older; it is estimated that more than 180 trials of CBD are ongoing in the United States for various indications.²⁶ A notable question in the development of CBD-based therapies is: What is the role of natural plant-derived CBD compared to a pure synthetic form of CBD? The latter is akin to a pharmaceutical process in which a single molecule is developed as the active drug.²⁷ Although the potency and composition of plant-derived CBD can vary with crop conditions, plant strains, and the extraction process, a synthetic molecule would allow for consistency in safety, potency, and pharmacokinetic properties, as well as efficacy, as a consequence.²⁶

There are intriguing data to suggest a potential use for topical CBD in the management of skin diseases, including acne vulgaris. Researchers have, for at least a decade, been investigating the role of the endocannabinoid system, which has physiologic regulatory functions in proliferation, differentiation, apoptosis and cytokine, mediator, and hormone production of various cell types in skin, hair follicles, and sebaceous glands.²⁸ Cannabidiol has been shown to suppress proliferation of sebocytes through activation of transient receptor potential vanilloid 4 ion channels and to have anti-inflammatory effects on sebocytes.²⁹ It has been shown to inhibit human keratinocyte proliferation through a non-CB1/CB2 mechanism³⁰ and to possess potent antimicrobial activity against gram-positive bacteria such as P acnes.³¹

Given these effects on sebocytes, modulation of keratinocyte proliferation, and anti-inflammatory and antibacterial effects, CBD could prove beneficial in the management of acne vulgaris. A new synthetic CBD topical formulation, BTX 1503, is under investigation for the treatment of acne vulgaris.

Early clinical data confirm both the anti-inflammatory effects of topical BTX 1503 as well as its effects on noninflammatory lesions, with 4-week reductions in inflammatory lesion counts similar to what are reported in clinical trials for leading FDA-approved topical therapies in the same time frame.

The phase 1b trial was a 4-week, open-label study in participants with moderate to severe acne vulgaris.³² The primary end point was safety, as demonstrated by the incidence of TEAE, laboratory monitoring, and assessment of cutaneous tolerability. Exploratory end points included changes in inflammatory and noninflammatory lesion counts and IGA score. A total of 21 participants aged 18 to 65 years with moderate to severe acne vulgaris were enrolled. BTX 1503 was applied topically twice daily. At baseline, eligible participants had 20 to 50 inflammatory lesions and 20 to 100 noninflammatory acne lesions on the face, an IGA of 3 (moderate) or 4 (severe), and 3 or fewer nodular or cystic lesions (>5 mm in diameter). No serious or severe TEAEs were reported; no participants withdrew due to a TEAE. Slight erythema, slight scaling, slight dryness, and slight burning and stinging were reported; there were no reports of irritant or allergic contact dermatitis. Only 1 TEAE was thought to be possibly related to treatment: mild pain at the application site.³²

In addition to presenting a potential new chemical entity for the topical treatment of acne, the novel topical vehicle formulation of BTX 1503 represents an innovative approach to drug delivery. The formulation utilizes proprietary technology to deliver high doses of drug into the skin without controversial penetration enhancers, preservatives, or other potential irritating additives. Instead, volatile excipients are used that evaporate upon application to the skin, leaving a so-called superconcentrated secondary formulation on the skin. The concentration gradient effect then drives the concentrated drug into skin. Although the formulation efficiently delivers active drug into the skin and its appendages, systemic exposure has been reported to be very low. A phase 2 randomized, double-blind, vehicle-controlled trial ongoing in the United States and Australia in 360 patients with moderate to severe acne vulgaris will provide key data to confirm the efficacy and safety of BTX 1503 (ClinicalTrials.gov Identifier NCT03573518).

Conclusion

Drug development continues to focus on the challenge of treating acne effectively and safely. Vehicle innovations are optimizing existing active drugs and creating opportunities to deliver new compounds to the skin. The approval of sarecycline as the first new chemical entity approved for acne in several years may be followed in coming years by other new actives, including clascoterone and CBD.